bluuebunny/crossref_metadata_2025_split huggingface dataset:
Selection and Characterization of Cyclic Peptides that Bind to a Monoclonal Antibody Against Meningococcal L3,7,9 lipopolysaccharides
Authors: Lauvrak V. , Berntzen G. , Heggelund U. , Herstad T. K. , Sandin R. H. , Dalseg R. , Rosenqvist E. , Sandlie I. , Michaelsen T. E. 
Published: March 2004

AbstractThere is still no general vaccine for prevention of disease caused by group‐B meningococcal strains. Meningococcal lipopolysaccharides (LPSs) have received attention as potential vaccine candidates, but concerns regarding their safety have been raised. Peptide mimics of LPS epitopes may represent safe alternatives to immunization with LPS. The monoclonal antibody (MoAb) 9‐2‐L3,7,9 [1] specific for Neisseria meningitidis LPS immunotype L3,7,9 is bactericidal and does not cross‐react with human tissue. To explore the possibility of isolating peptide mimics of the epitope recognized by MoAb 9‐2‐L3,7,9, we have constructed two phage display libraries of six and nine random amino acids flanked by cysteines. Furthermore, we developed a system for the easy exchange of peptide‐encoding sequences from the phage‐display system to a hepatitis B core (HBc) expression system. Cyclic peptides that specifically bound MoAb 9‐2‐L3,7,9 at a site overlapping with the LPS‐binding site were selected from both libraries. Three out of four tested peptides which reacted with MoAb 9‐2‐L3,7,9 were successfully presented as fusions to the immunodominant loop of HBc particles expressed in Escherichia coli. However, both peptide conjugates to keyhole limpet haemocyanin and HBc particle fusions failed to give an anti‐LPS response in mice.
EFFECTS OF MORPHINE ON METHOTREXATE DISPOSITION IN MICE
Authors: Li Yuai , Looney Greg A , Hurwitz Aryeh 
Published: March 2004

SUMMARY1. Morphine has been shown to slow the renal excretion of other drugs. The present study in mice evaluated the effects of morphine on the disposition of methotrexate (MTX), an antimetabolite eliminated by the kidneys.2. Mice were injected with morphine (20 mg/kg) or saline s.c. After 30 min, 20–80 mg/kg MTX was injected i.v. Blood and urine samples were assayed for MTX by HPLC.3. Morphine reduced plasma clearance (CL) of MTX from 0.147 ± 0.015 to 0.061 ± 0.009 mL/min per g bodyweight (P < 0.01). The area under the plasma concentration–time curve (AUC0–∞) was raised by morphine from 151 ± 18 to 369 ± 36 µg·mL per min (P < 0.01). Without morphine administration, 22–27% of an MTX dose was excreted into the urine in 30 min. The corresponding fractions excreted into the urine after morphine were reduced to 15–18% (P < 0.01).4. Plasma levels of MTX administered intravenously to mice are elevated by the concomitant administration of morphine, which reduces renal elimination of MTX.
NITRIC OXIDE DOES NOT MEDIATE PROMOTION OF CELLULAR POTASSIUM RELEASE BY PHENOLPHTHALEIN IN COS‐7 CELLS
Authors: Mason Robert W , Hopp Laszlo , Lloyd John B 
Published: March 2004

SUMMARY1. It has been proposed that phenolphthalein exerts its laxative effect via an intracellular cascade that begins with the activation of nitric oxide synthase (NOS) and ends with an inhibition of NaCl and water reabsorption from the colon. Phenolphthalein also promotes the release of potassium from cells, but it is not known how this is related to its effect on sodium and water uptake.2. An established in vitro system was used to examine the role of nitric oxide (NO) in phenolphthalein‐induced release of 86Rb+ from COS‐7 cells.3. Sodium nitroprusside, an NOS‐independent NO source, was unable to mimic the effects of phenolphthalein and NG‐nitro‐l‐arginine methyl ester, an NOS inhibitor, was unable to block the effect of phenolphthalein.4. It is concluded that NO generation is not required for phenolphthalein‐stimulated potassium release. It is proposed that the effect of phenolphthalein on cellular potassium release is mechanistically distinct from the effect on NaCl and water uptake by colonocytes.
A fuzzy derivative approach to classification of outcomes from the ADRAC database
Authors: Mamedov M.A. , Saunders G.W. , Yearwood J. 
Published: March 2004

AbstractThe Australian Adverse Drug Reaction Advisory Committee (ADRAC) database has been collected and maintained by the Therapeutic Goods Administration. In this paper we study a part of his database (Card2) which contains records having just reactions from the Cardiovascular group. Drug‐reaction relationships are presented by a vector of degrees which shows the degree of association of a drug with each class of reactions. In this work we examine these relationships in the classification of reaction outcomes. A modified version of the fuzzy derivative method (FDM2) is used for classification.
Role of Purine Nucleoside Phosphorylase in Interactions between 2′,3′-Dideoxyinosine and Allopurinol, Ganciclovir, or Tenofovir
Authors: Ray Adrian S. , Olson Loren , Fridland Arnold 
Published: March 2004

ABSTRACT

The level of systemic exposure to 2′,3′-dideoxyinosine (ddI) is increased 40 to 300% when it is coadministered with allopurinol (Allo), ganciclovir (GCV), or tenofovir. However, the mechanism for these drug interactions remains undefined. A metabolic route for ddI clearance is its breakdown by purine nucleoside phosphorylase (PNP). Consistent with previous reports, enzymatic inhibition assays showed that acyclic nucleotide analogs can inhibit the phosphorolysis of inosine. It was further established that the mono- and diphosphate forms of tenofovir were inhibitors of PNP-dependent degradation of ddI (

K
i

s, 38 nM and 1.3 μM, respectively). Allo and its metabolites were found to be relatively weak inhibitors of PNP (

K
i

s, >100 μM). Coadministration of tenofovir, GCV, or Allo decreased the amounts of intracellular ddI breakdown products in CEM cells, while they increased the ddI concentrations (twofold increase with each drug at approximately 20 μM). While inhibition of the physiological function of PNP is unlikely due to the ubiquitous presence of high levels of enzymatic activity, phosphorylated metabolites of GCV and tenofovir may cause the increased level of exposure to ddI by direct inhibition of its phosphorolysis by PNP. The discrepancy between the cellular activity of Allo and the weak enzyme inhibition by Allo and its metabolites may be explained by an indirect mechanism of PNP inhibition. This mechanism may be facilitated by the unfavorable equilibrium of PNP and the buildup of one of its products (hypoxanthine) through the inhibition of xanthine oxidase by Allo. These findings support the inhibition of PNP-dependent ddI degradation as the molecular mechanism of these drug interactions.
In Vivo Detection and Quantification of Tetracycline by Use of a Whole-Cell Biosensor in the Rat Intestine
Authors: Bahl Martin Iain , Hansen Lars Hestbjerg , Licht Tine Rask , Sørensen Søren J. 
Published: March 2004

ABSTRACT

An
Escherichia coli
biosensor strain, harboring the plasmid pTGFP2, was introduced into the gastrointestinal tract of gnotobiotic rats that continuously received drinking water containing tetracycline. Plasmid pTGFP2 contains a transcriptional fusion between a green fluorescent protein (GFP) gene and a tetracycline-regulated promoter and was shown to produce a proportional GFP signal in response to exposure to various tetracycline concentrations when harbored by an
E. coli
strain. The plasmid was highly unstable in the host bacteria colonizing the intestinal system of the animals, and rapid plasmid loss was observed. Reintroduction of the
E. coli
MC4100/pTGFP2 strain into animals already colonized by the plasmid-free
E. coli
strain the day before euthanasia made it possible to extract and analyze the biosensors from intestinal samples. The induction of GFP in the biosensor cells extracted from the animals was estimated on a single-cell basis by use of flow cytometry, and the mean induction of GFP in the samples was compared to a standard curve prepared from known tetracycline concentrations. The results showed that the bioavailable tetracycline concentration within the bacterial growth habitat of the intestine was proportional to the concentration of tetracycline in drinking water but represented only approximately 0.4% of the intake concentration. This is a significant finding which will help to clarify antimicrobial therapy in the intestinal environment.
Efficacy of Dalbavancin against Methicillin-Resistant
Staphylococcus aureus
in the Rat Granuloma Pouch Infection Model
Authors: Jabés Daniela , Candiani Gianpaolo , Romanó Gabriella , Brunati Cristina , Riva Simona , Cavaleri Marco 
Published: March 2004

ABSTRACT

Infections due to methicillin-resistant
Staphylococcus aureus
(MRSA) are an important cause of morbidity and mortality in hospital patients. Moreover, increased incidences of outpatient MRSA have been recently reported. This study investigated the bactericidal activity of dalbavancin, a novel, semisynthetic glycopeptide antibiotic, against methicillin-sensitive
S. aureus
(MSSA) and MRSA in the rat granuloma pouch infection model. A single intravenous dose of 10 mg of dalbavancin/kg of body weight reduced the viable MRSA count in pouch exudates by more than 2 log CFU/ml, and regrowth was prevented for up to 120 h. Comparable results with vancomycin required four 100-mg/kg intramuscular doses. With one or two doses of vancomycin, the bacterial load declined over proportionately shorter periods of time, followed by regrowth. Reduction of the bacterial load obtained with 100- and 200-mg/kg oral doses of linezolid was relatively transient, with regrowth starting at 48 h. A single 10-mg/kg dose of dalbavancin reduced the MSSA count at 24 h to below the limit of detection, with no regrowth for at least 96 h. Dalbavancin demonstrated good exudate penetration; the ratio of the area under the curve (AUC) in plasma to the AUC in pouch exudate was 1.01. The in vivo activity of dalbavancin in this model is consistent with the antibiotic concentrations that are reached and maintained for extended periods of time after a single 10-mg/kg dose and with in vitro data showing that these concentrations are bactericidal for staphylococci. The pharmacokinetic and efficacy data seen in this relevant model of infection suggest that dalbavancin may be administered less frequently than vancomycin and linezolid.
In Vitro Activities of 28 Antimicrobial Agents against
Staphylococcus aureus
Isolates from Tertiary-Care Hospitals in Korea: a Nationwide Survey
Authors: Kim Hong Bin , Jang Hee-Chang , Nam Hee Jung , Lee Yeong Seon , Kim Bong Su , Park Wan Beom , Lee Ki Deok , Choi Young Joo , Park Sang Won , Oh Myoung-don , Kim Eui-Chong , Choe Kang Won 
Published: March 2004

ABSTRACT

Staphylococcus aureus
, one of the most frequently isolated pathogens in both hospitals and the community, has been particularly efficient at developing resistance to antimicrobial agents. As methicillin-resistant
S. aureus
(MRSA) has prevailed and, furthermore, as
S. aureus
with reduced susceptibility to vancomycin has emerged, the therapeutic options for the treatment of
S. aureus
infections have become limited. To update the current status of antibiotic resistance, clinical
S. aureus
isolates were collected from eight university-affiliated hospitals from June 1999 to January 2001. Susceptibility tests with 28 antibiotics were performed by the disk diffusion method. Among a total of 682 isolates, the methicillin resistance rate was 64% (439 of 682), and most of the MRSA isolates were resistant to multiple classes of antibiotics. Although a constitutive macrolide-lincosamide-streptogramin B resistance phenotype was common, no isolates were resistant to quinupristin-dalfopristin or linezolid. Rifampin, fusidic acid, trimethoprim-sulfamethoxazole, and arbekacin showed superior in vitro activity compared with the other antibiotics against the MRSA isolates. No isolates showed reduced susceptibility to vancomycin.
BpeAB-OprB, a Multidrug Efflux Pump inBurkholderia pseudomallei
Authors: Chan Y. Y. , Tan T. M. C. , Ong Y. M. , Chua K. L. 
Published: March 2004

ABSTRACTBurkholderia pseudomallei, the causative agent of melioidosis, is intrinsically resistant to a wide range of antimicrobial agents, including β-lactams, aminoglycosides, macrolides, and polymyxins. An operon,bpeR-bpeA-bpeB-oprB, which encodes a putative repressor, a membrane fusion protein, an inner membrane protein, and an outer membrane protein, respectively, of a multidrug efflux pump of the resistance-nodulation-division family was identified inB. pseudomallei. The divergently transcribedbpeRgene encodes a putative repressor protein of the TetR family which probably regulates the expression of thebpeAB-oprBgene cluster. Comparison of the MICs and minimal bactericidal concentrations of antimicrobials forbpeABdeletion mutant KHWΔbpeABand its isogenic wild-type parent, KHW, showed that theB. pseudomalleiBpeAB-OprB pump is responsible for the efflux of the aminoglycosides gentamicin and streptomycin, the macrolide erythromycin, and the dye acriflavine. Antibiotic efflux by the BpeAB-OprB pump was dependent on a proton gradient and differs from that by the AmrAB-OprA pump in that it did not efflux the aminoglycoside spectinomycin or the macrolide clarithromycin. The broad-spectrum efflux pump inhibitor MC-207,110 did not potentiate the effectiveness of the antimicrobials erythromycin and streptomycin inB. pseudomallei.
Expression ofacrB,acrF,acrD,marA, andsoxSinSalmonella entericaSerovar Typhimurium: Role in Multiple Antibiotic Resistance
Authors: Eaves Deborah J. , Ricci Vito , Piddock Laura J. V. 
Published: March 2004

ABSTRACTComparative reverse transcription-PCR in combination with denaturing high-pressure liquid chromatography analysis was used to determine the levels of expression ofsoxS,marA,acrF,acrB, andacrDin multiple-antibiotic-resistant (MAR)Salmonella entericaserovar Typhimurium isolates and mutants ofS. entericaserovar Typhimurium SL1344 with defined deletions. Posttherapy MAR clinical isolates had increased levels of expression of all genes exceptsoxS. S. entericaserovar Typhimurium SL1344 ΔacrBexpressed 7.9-fold moreacrFthan the parent strain. A strain with anacrFdeletion expressed 4.6-fold moreacrB. Deletion ofacrBand/oracrFresulted in 2.7- to 4.3-fold moremarAmRNA and 3.6- to 4.9-fold increases in the levels of expression ofacrDbut had a variable effect on the expression ofsoxS. All mutants were hypersusceptible to antibiotics, dyes, and detergents; but the MIC changes were more noticeable for SL1344 with theacrBdeletion than for the mutant with theacrFdisruption. These mutants had different but overlapping phenotypes, and the concentrations of ciprofloxacin accumulated by the mutants were different. These data suggest thatacrB,acrF, andacrDare coordinately regulated and that their expression influences the expression of the transcriptional activatorsmarAandsoxS.
CFE-1, a Novel Plasmid-Encoded AmpC β-Lactamase with anampRGene Originating fromCitrobacter freundii
Authors: Nakano Ryuichi , Okamoto Ryoichi , Nakano Yumiko , Kaneko Kenichi , Okitsu Naohiro , Hosaka Yoshio , Inoue Matsuhisa 
Published: March 2004

ABSTRACTA clinical isolate ofEscherichia colifrom a patient in Japan, isolate KU6400, was found to produce a plasmid-encoded β-lactamase that conferred resistance to extended-spectrum cephalosporins and cephamycins. Resistance arising from production of a β-lactamase could be transferred by either conjugation or transformation with plasmid pKU601 intoE. coliML4947. The substrate and inhibition profiles of this enzyme resembled those of the AmpC β-lactamase. The resistance gene of pKU601, which was cloned and expressed inE. coli, proved to contain an open reading frame showing 99.8% DNA sequence identity with theampCgene ofCitrobacter freundiiGC3. DNA sequence analysis also identified a gene upstream ofampCwhose sequence was 99.0% identical to theampRgene fromC. freundiiGC3. In addition, a fumarate operon (frdABCD) and an outer membrane lipoprotein (blc) surrounding theampR-ampCgenes inC. freundiiwere identified, and insertion sequence (IS26) elements were observed on both sides of the sequences identified (forming an IS26composite transposon); these results confirm the evidence of the translocation of a β-lactamase-associated gene region from the chromosome to a plasmid. Finally, we describe a novel plasmid-encoded AmpC β-lactamase, CFE-1, with anampRgene derived fromC. freundii.
Population Pharmacokinetics of Arbekacin, Vancomycin, and Panipenem in Neonates
Authors: Kimura Toshimi , Sunakawa Keisuke , Matsuura Nobuo , Kubo Hiroaki , Shimada Shigehiko , Yago Kazuo 
Published: March 2004

ABSTRACT

Immature renal function in neonates requires antibiotic dosage adjustment. Population pharmacokinetic studies were performed to determine the optimal dosage regimens for three types of antibiotics: an aminoglycoside, arbekacin; a glycopeptide, vancomycin; and a carbapenem, panipenem. Eighty-three neonates received arbekacin (
n
= 41), vancomycin (
n
= 19), or panipenem (
n
= 23). The postconceptional ages (PCAs) were 24.1 to 48.4 weeks, and the body weights (BWs) ranged from 458 to 5,200 g. A one-compartment open model with first-order elimination was applied and evaluated with a nonlinear mixed-effect model for population pharmacokinetic analysis. In the fitting process, the fixed effects significantly related to clearance (CL) were PCA, postnatal age, gestational age, BW, and serum creatinine level; and the fixed effect significantly related to the volume of distribution (
V
) was BW. The final formulas for the population pharmacokinetic parameters are as follows: CL
arbekacin
= 0.0238 × BW/serum creatinine level for PCAs of <33 weeks and CL
arbekacin
= 0.0367 × BW/serum creatinine level for PCAs of ≥33 weeks,
V
arbekacin
= 0.54 liters/kg, CL
vancomycin
= 0.0250 × BW/serum creatinine level for PCAs of <34 weeks and CL
vancomycin
= 0.0323 × BW/serum creatinine level for PCAs of ≥34 weeks,
V
vancomycin
= 0.66 liters/kg, CL
panipenem
= 0.0832 for PCAs of <33 weeks and CL
panipenem
= 0.179 × BW for PCAs of ≥33 weeks, and
V
panipenem
= 0.53 liters/kg. When the CL of each drug was evaluated by the nonlinear mixed-effect model, we found that the mean CL for subjects with PCAs of <33 to 34 weeks was significantly smaller than those with PCAs of ≥33 to 34 weeks, and CL showed an exponential increase with PCA. Many antibiotics are excreted by glomerular filtration, and maturation of glomerular filtration is the most important factor for estimation of antibiotic clearance. Clinicians should consider PCA, serum creatinine level, BW, and chemical features when determining the initial antibiotic dosing regimen for neonates.
Pseudomonas aeruginosa
Biofilms Exposed to Imipenem Exhibit Changes in Global Gene Expression and β-Lactamase and Alginate Production
Authors: Bagge Niels , Schuster Martin , Hentzer Morten , Ciofu Oana , Givskov Michael , Greenberg Everett Peter , Høiby Niels 
Published: March 2004

ABSTRACT

The lungs of cystic fibrosis (CF) patients are commonly colonized with
Pseudomonas aeruginosa
biofilms. Chronic endobronchial
P. aeruginosa
infections are impossible to eradicate with antibiotics, but intensive suppressive antibiotic therapy is essential to maintain the lung function of CF patients. The treatment often includes β-lactam antibiotics. How these antibiotics influence gene expression in the surviving biofilm population of
P. aeruginosa
is not clear. Thus, we used the microarray technology to study the effects of subinhibitory concentrations of a β-lactam antibiotic, imipenem, on gene expression in biofilm populations. Many genes showed small but statistically significant differential expression in response to imipenem. We identified 34 genes that were induced or repressed in biofilms exposed to imipenem more than fivefold compared to the levels of induction or repression for the controls. As expected, the most strongly induced gene was
ampC
, which codes for chromosomal β-lactamase. We also found that genes coding for alginate biosynthesis were induced by exposure to imipenem. Alginate production is correlated to the development of impaired lung function, and
P. aeruginosa
strains isolated from chronically colonized lungs of CF patients are nearly always mucoid due to the overproduction of alginate. Exposure to subinhibitory concentrations of imipenem caused structural changes in the biofilm, e.g., an increased biofilm volume. Increased levels of alginate production may be an unintended adverse consequence of imipenem treatment in CF patients.
Efficacy, Safety, and Plasma Pharmacokinetics of Escalating Dosages of Intravenously Administered Ravuconazole Lysine Phosphoester for Treatment of Experimental Pulmonary Aspergillosis in Persistently Neutropenic Rabbits
Authors: Petraitiene Ruta , Petraitis Vidmantas , Lyman Caron A. , Groll Andreas H. , Mickiene Diana , Peter Joanne , Bacher John , Roussillon Kristin , Hemmings Melissa , Armstrong Derrek , Avila Nilo A. , Walsh Thomas J. 
Published: March 2004

ABSTRACT

Ravuconazole is a new antifungal triazole with broad-spectrum activity and a long half-life in plasma. We studied the antifungal efficacy, safety, and pharmacokinetics of ravuconazole lysine phosphoester in escalating dosages for the treatment of invasive pulmonary aspergillosis due to
Aspergillus fumigatus
in persistently neutropenic rabbits. Treatment groups consisted of rabbits treated with ravuconazole at 2.5 (RVC2.5), 5 (RVC5), and 10 (RVC10) mg/kg of body weight/day, rabbits treated with amphotericin B (AMB) at 1 mg/kg/day, or untreated controls. There was a dose-dependent reduction of pulmonary residual fungal burden (CFU per gram) in RVC5-, RVC10-, and AMB-treated rabbits in comparison to untreated controls (
P
< 0.01,
P
< 0.001, and
P
< 0.01, respectively). These findings correlated with progressive galactomannan antigenemia in untreated controls and the RVC2.5-treated rabbits, a lower galactomannan index (GMI) in RVC5- and RVC10-treated rabbits, and a similarly low GMI in AMB-treated rabbits (
P
< 0.01). Rabbits treated with RVC5, RVC10, and AMB also showed a reduction of organism-mediated pulmonary injury, as measured by infarct scores and lung weights, in comparison to untreated controls (
P
< 0.001). These results were supported by decreased pulmonary infiltrates detected by computed tomography in RVC5- and RVC10-treated rabbits in comparison to untreated controls (
P
< 0.05). Survival throughout the entire study was achieved in 95% of RVC5-treated rabbits (
P
< 0.001), 85% of RVC10-treated rabbits (
P
< 0.001), and 50% of AMB-treated rabbits (
P
< 0.05) in comparison to none of the untreated controls. Ravuconazole showed linear plasma pharmacokinetics and a large volume of distribution while maintaining concentrations in plasma above the MIC throughout the dosing interval. There was no evidence of hepatotoxicity or nephrotoxicity among ravuconazole-treated animals. Intravenously administered ravuconazole lysine phosphoester showed dose-dependent efficacy and an excellent safety profile for the treatment of invasive pulmonary aspergillosis in persistently neutropenic rabbits.