bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activities of Tizoxanide and Nitazoxanide Compared to Those of Five Other Thiazolides and Three Other Agents against Anaerobic Species
Authors: Pankuch Glenn A. , Appelbaum Peter C. 
Published: February 2006

ABSTRACT
Agar dilution was used, and MICs of metronidazole, tizoxanide, nitazoxanide, denitrotizoxanide, RM 4803, RM 4807, RM 4809, RM 4819, amoxicillin-clavulanate, and clindamycin were measured against 412 anaerobes. Nitazoxanide, tizoxanide, RM 4807, and RM 4809 were active against all groups, except for gram-positive non-spore-forming rods with 50% minimum inhibitory concentrations (when the latter were excluded) of 1 to 2 μg/ml and 90% minimum inhibitory concentrations of 4 to 8 μg/ml, respectively. Metronidazole MICs were usually lower against all groups except clostridia.
Lack of Evidence for In Vivo Transformation of Zidovudine Triphosphate to Stavudine Triphosphate in Human Immunodeficiency Virus-Infected Patients
Authors: Meléndez Margarita , Blanco Raúl , Delgado Wilfredo , García Rosario , Santana Jorge , García Hermes , Rosario Osvaldo , Rodríguez José F. 
Published: February 2006

ABSTRACT

The in vivo and in vitro determination of significant intracellular stavudine (d4T) triphosphate (d4TTP) concentrations in human immunodeficiency virus (HIV)-infected subjects and NS-1 cells treated with zidovudine (ZDV) has recently been reported. This study was conducted to corroborate these findings with in vivo samples from HIV-infected subjects taking ZDV and in vitro CEM
SS
cells incubated with different ZDV concentrations. Previously, we have reported on our validated high-performance liquid chromatography coupled with tandem mass spectrometry methodology for the simultaneous determination of d4TTP, lamivudine triphosphate, and ZDV triphosphate (ZDVTP) concentrations. Using this methodology, we monitored the d4TTP concentration in more than 100 samples from HIV-infected subjects treated with d4T. In addition, we simultaneously monitored the concentrations of d4TTP and ZDVTP in more than 500 samples from HIV-infected individuals who were taking ZDV. Finally, we performed in vitro studies by incubating CEM
SS
cells with 10 μM, 50 μM, and 100 μM ZDV and monitored the formation of d4TTP at 24 and 48 h. We could measure d4TTP concentrations from HIV-infected individuals with a limit of quantitation (LOQ) of 2.7 fmol/10
6
cells (total injection, 54 fmol). In the in vivo studies, we measured the d4TTP concentrations among patients receiving d4T treatment, but the samples from patients taking ZDV did not provide d4TTP concentrations above the LOQ. Furthermore, in vitro samples did not produce any signal for d4TTP, despite the detection of substantial ZDVTP concentrations in CEM
SS
cells. Thus, contrary to the previous report, we found no evidence for the in vivo or in vitro transformation of ZDVTP to d4TTP in HIV-infected subjects or CEM
SS
cells.
Structural Correlates of Antibacterial and Membrane-Permeabilizing Activities in Acylpolyamines
Authors: Balakrishna Rajalakshmi , Wood Stewart J. , Nguyen Thuan B. , Miller Kelly A. , Suresh Kumar E. V. K. , Datta Apurba , David Sunil A. 
Published: February 2006

ABSTRACTA homologous series of mono- and bis-acyl polyamines with varying acyl chain lengths originally synthesized for the purpose of sequestering lipopolysaccharide were evaluated for antimicrobial activity to test the hypothesis that these bis-cationic amphipathic compounds may also bind to and permeabilize intact gram-negative bacterial membranes. Some compounds were found to possess significant antimicrobial activity, mediated via permeabilization of bacterial membranes. Structure-activity relationship studies revealed a strong dependence of the acyl chain length on antimicrobial potency and permeabilization activity. Homologated spermine, bis-acylated with C8or C9chains, was found to profoundly sensitizeEscherichia colito hydrophobic antibiotics such as rifampin. Nonspecific cytotoxicity is a potential drawback of these membranophilic compounds. However, the surface activity of these cationic amphipaths is strongly attenuated under physiological conditions via binding to serum albumin. Significant antibacterial activity is still retained in the presence of physiological concentrations of human serum albumin, suggesting that these compounds may serve as leads in the development of novel adjuncts to conventional antimicrobial chemotherapy.
Pharmacokinetics of Telbivudine following Oral Administration of Escalating Single and Multiple Doses in Patients with Chronic Hepatitis B Virus Infection: Pharmacodynamic Implications
Authors: Zhou Xiao-Jian , Lim Seng-Gee , Lloyd Deborah M. , Chao George C. , Brown Nathaniel A. , Lai Ching-Lung 
Published: February 2006

ABSTRACT

The pharmacokinetics of telbivudine were evaluated in adult patients with chronic hepatitis B virus (HBV) infection following once-daily oral administration at escalating doses of 25, 50, 100, 200, 400, and 800 mg/day for 4 weeks. Telbivudine was rapidly absorbed after oral administration, with the median times
T
max
to the maximum plasma concentration (
C
max
) ranging from 0.8 to 3.0 h postdosing across cohorts. Single-dose and steady-state maximum
C
max
s and the areas under the plasma concentration-time curve from time zero to time
t
(AUC

0-
t

s) increased proportionally with dose. At steady-state, the values of
C
max
and AUC

0-
t

were higher than those obtained after the administration of a single dose, indicative of a slight accumulation, with the ratios of the steady-state value to the value after the administration of a single dose ranging from 1.14 to 1.49 for
C
max
and from 1.40 to 1.70 for AUC

0-
t

. While the elimination of telbivudine from plasma was apparently monophasic over the 8-h sampling period, the substantial steady-state trough plasma levels observed in the groups receiving doses of 100 to 800 mg were clearly indicative of the presence of a second slower elimination phase, with the mean estimated half-lives ranging from 29.5 to 41.3 h by compartmental modeling analysis. Pharmacokinetic and pharmacodynamic analyses by using maximum-effect modeling established a quantitative relationship between a reduction in serum HBV DNA levels and parameters of drug exposure, in particular, the steady-state
C
max
and AUC

0-
t

. In summary, this study showed that telbivudine exhibits dose-proportional plasma pharmacokinetics with sustained steady-state drug exposure and exposure-related antiviral activity, supporting the need for further clinical studies by use of a once-daily regimen in patients with chronic HBV infection.
Interlaboratory Comparison of PCR-Based Methods for Detection of Penicillin G Susceptibility in
Neisseria meningitidis
Authors: Taha Muhamed-Kheir , Zarantonelli Maria Leticia , Neri Arianna , Enriquez Rocío , Vázquez Julio A. , Stefanelli Paola 
Published: February 2006

ABSTRACT

We carried out a study for the nonculture detection of susceptibility of
Neisseria meningitis
to penicillin G in three laboratories of the European Monitoring Group on Meningococci (EMGM). Thirteen clinical samples (cerebrospinal fluids) and corresponding bacterial isolates from 13 cases of invasive meningococcal infection were distributed to the three laboratories. The MICs of penicillin G were determined for the isolates. Each laboratory used an “in-house” PCR-based method to determine alterations to the
penA
gene, which is associated with a reduced susceptibility to penicillin G. Nucleotide sequences from the 3′ end of the
penA
gene were also determined. We observed a good correlation between genotyping of
penA
and the phenotypic determination (MIC) of susceptibility to penicillin G. The results obtained by the three methods for
penA
in the samples correlated very well with those obtained in bacterial isolates and with sequence data. The kappa coefficient that was used to estimate the level of agreement between genotypic results varied between 0.65 and 1, indicating a good agreement. This suggests that genotyping can predict susceptibility of
N. meningitidis
to penicillin G. These data strongly suggest that genotyping of
penA
should be used to determine meningococcal susceptibility to penicillin G in culture-negative cases. Although the nucleotide sequence of
penA
may be the gold standard in genotyping of
penA
, the less expensive PCR-based approach reported in this study may be quicker when a large number of isolates and clinical samples need to be tested.
Effect of Efflux on Telithromycin and Macrolide Susceptibility in
Haemophilus influenzae
Authors: Bogdanovich Tatiana , Bozdogan Bülent , Appelbaum Peter C. 
Published: February 2006

ABSTRACT

This study investigated the presence of telithromycin and azithromycin efflux in 58 clinical strains of
Haemophilus influenzae
with various susceptibilities to macrolides, azalides, and ketolides. Efflux pumps were studied by measuring accumulation of radioactive [
3
H]telithromycin and [
N
-methyl-
3
H]azithromycin in the presence and absence of carbonyl
m
-chlorophenylhydrazone (CCCP), a protonophore. In 17 strains for which the telithromycin MICs were 0.06 to 0.5 μg/ml (azithromycin MICs, ≤0.06 to 0.125 μg/ml; clarithromycin MICs, ≤0.06 to 2 μg/ml), telithromycin and azithromycin accumulations were high without CCCP and not affected by its addition, which indicates absence of efflux. In 22 strains for which the telithromycin MICs were 0.25 to 4 μg/ml (azithromycin MICs, 0.25 to 1 μg/ml; clarithromycin MICs, 1 to 8 μg/ml), initially low levels of telithromycin accumulation became higher after addition of CCCP, indicating a functioning efflux pump. Nineteen strains for which the telithromycin MICs were ≥2 μg/ml had efflux as well as various mutations in ribosomal proteins L4, L22, and/or 23S rRNA (domains II and V). Of these 19 strains, the telithromycin MICs (≥8 μg/ml) for 17 of them were significantly raised (azithromycin, MICs 4 to >32 μg/ml; clarithromycin MICs, 8 to >32 μg/ml). From these results we conclude that telithromycin efflux with or without additional ribosomal alterations is present in all
H. influenzae
strains, except for those for which the telithromycin MICs were very low.
Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease
Authors: Perni Robert B. , Almquist Susan J. , Byrn Randal A. , Chandorkar Gurudatt , Chaturvedi Pravin R. , Courtney Lawrence F. , Decker Caroline J. , Dinehart Kirk , Gates Cynthia A. , Harbeson Scott L. , Heiser Angela , Kalkeri Gururaj , Kolaczkowski Elaine , Lin Kai , Luong Yu-Ping , Rao B. Govinda , Taylor William P. , Thomson John A. , Tung Roger D. , Wei Yunyi , Kwong Ann D. , Lin Chao 
Published: February 2006

ABSTRACT

VX-950 is a potent, selective, peptidomimetic inhibitor of the hepatitis C virus (HCV) NS3-4A serine protease, and it demonstrated excellent antiviral activity both in genotype 1b HCV replicon cells (50% inhibitory concentration [IC
50
] = 354 nM) and in human fetal hepatocytes infected with genotype 1a HCV-positive patient sera (IC
50
= 280 nM). VX-950 forms a covalent but reversible complex with the genotype 1a HCV NS3-4A protease in a slow-on, slow-off process with a steady-state inhibition constant (

K
i

*) of 7 nM. Dissociation of the covalent enzyme-inhibitor complex of VX-950 and genotype 1a HCV protease has a half-life of almost an hour. A >4-log
10
reduction in the HCV RNA levels was observed after a 2-week incubation of replicon cells with VX-950, with no rebound of viral RNA observed after withdrawal of the inhibitor. In several animal species, VX-950 exhibits a favorable pharmacokinetic profile with high exposure in the liver. In a recently developed HCV protease mouse model, VX-950 showed excellent inhibition of HCV NS3-4A protease activity in the liver. Therefore, the overall preclinical profile of VX-950 supports its candidacy as a novel oral therapy against hepatitis C.
Rate of Elimination of
Wolbachia pipientis
by Doxycycline In Vitro Increases following Drug Withdrawal
Authors: Makepeace Benjamin L. , Rodgers Lisa , Trees Alexander J. 
Published: February 2006

ABSTRACT

Wolbachia pipientis
is an obligate intracellular bacterium within the family
Anaplasmataceae
that infects many terrestrial arthropods and arthropod-transmitted nematodes (filariae). Several filarial species are major human pathogens, and antibiotics with activity against
Wolbachia
offer a promising new therapeutic approach, since the adult worms are relatively refractory to conventional anthelmintics but depend on
Wolbachia
for reproduction and viability. In a natural filarial parasite of cattle,
Onchocerca ochengi
, intermittent chemotherapy is adulticidal whereas the equivalent dose administered as a continuous treatment is not. To investigate this further and to aid the design of efficacious regimens for human therapy, we used
Wolbachia
-infected
Aedes albopictus
mosquito cells in vitro. Here, we describe for the first time the accelerated depletion of bacteria after antibiotic withdrawal relative to the rate of elimination in the continuous presence of the drug. Mosquito cells were incubated with doxycycline while changes in 16S (bacterial) and 18S (host) rRNA and rRNA genes were determined by quantitative PCR assays. In cultures treated for 7 or 14 days followed by 7 days of drug withdrawal, the
Wolbachia
-to-
Aedes
rRNA ratio declined by ∼6 log, whereas immediately after 14 or 21 days of continuous treatment, the reduction was only ∼4 log (
P
< 0.05). However, low levels of 16S rRNA remained after 21 days of treatment, irrespective of whether doxycycline was withdrawn. Application of similar methodology to related intracellular bacteria may reveal that this posttreatment effect is not restricted to
Wolbachia
and could have wider implications for the design of intermittent regimens for antibiotic chemotherapy.
Pharmacokinetic and Safety Evaluation of High-Dose Combinations of Fosamprenavir and Ritonavir
Authors: Shelton Mark J. , Wire Mary Beth , Lou Yu , Adamkiewicz Brigette , Min Sherene S. 
Published: February 2006

ABSTRACT

High-dose combinations of fosamprenavir (FPV) and ritonavir (RTV) were evaluated in healthy adult subjects in order to select doses for further study in multiple protease inhibitor (PI)-experienced patients infected with human immunodeficiency virus type 1. Two high-dose regimens, FPV 1,400 mg twice a day (BID) plus RTV 100 mg BID and FPV 1,400 mg BID plus RTV 200 mg BID, were planned to be compared to the approved regimen, FPV 700 mg BID plus RTV 100 mg BID, in a randomized three-period crossover study. Forty-two healthy adult subjects were enrolled, and 39 subjects completed period 1. Due to marked hepatic transaminase elevations, predominantly with FPV 1,400 mg BID plus RTV 200 mg BID, the study was terminated prematurely. For FPV 1,400 mg BID plus RTV 100 mg BID, the values for plasma amprenavir (APV) area under the concentration-time profile over the dosing interval (τ) at steady state [AUC
(0-τ)
], maximum concentration of drug in plasma (
C
max
), and plasma concentration at the end of τ at steady state (
C
τ
) were 54, 81, and 26% higher, respectively, and the values for plasma RTV AUC
(0-τ)
,
C
max
, and
C
τ
were 49% higher, 71% higher, and 11% lower, respectively, than those for FPV 700 mg BID plus RTV 100 mg BID. For FPV 1,400 mg BID plus RTV 200 mg BID, the values for plasma APV AUC
(0-τ)
,
C
max
, and
C
τ
were 26, 48, and 32% higher, respectively, and the values for plasma RTV AUC
(0-τ)
,
C
max
, and
C
τ
increased 4.15-fold, 4.17-fold, and 3.99-fold, respectively, compared to those for FPV 700 mg BID plus RTV 100 mg BID. FPV 1,400 mg BID plus RTV 200 mg BID is not recommended due to an increased rate of marked hepatic transaminase elevations and lack of pharmacokinetic advantage. FPV 1,400 mg BID plus RTV 100 mg BID is currently under clinical evaluation in multiple PI-experienced patients.
Population Pharmacokinetics of Liposomal Amphotericin B in Pediatric Patients with Malignant Diseases
Authors: Hong Ying , Shaw Peter J. , Nath Christa E. , Yadav Satya P. , Stephen Katherine R. , Earl John W. , McLachlan Andrew J. 
Published: February 2006

ABSTRACT

A population pharmacokinetic model of liposomal amphotericin B (L-AmB) in pediatric patients with malignant diseases was developed and evaluated. Blood samples were collected from 39 pediatric oncology patients who received multiple doses of L-AmB with a dose range from 0.8 to 5.9 mg/kg of body weight/day. The patient cohort had an average age of 7 years (range, 0.2 to 17 years) and weighed an average of 28.8 ± 19.8 kg. Population pharmacokinetic analyses were performed with NONMEM software. Pharmacokinetic parameters, interindividual variability (IIV), between-occasion variability (BOV), and intraindividual variability were estimated. The influence of patient characteristics on the pharmacokinetics of L-AmB was explored. The final population pharmacokinetic model was evaluated by using a bootstrap sampling technique. The L-AmB plasma concentration-time data was described by a two-compartment pharmacokinetic model with zero-order input and first-order elimination. The population mean estimates of clearance (CL) and volume of distribution in the central compartment (
V
1
) were 0.44 liters/h and 3.12 liters, respectively, and exhibited IIV (CL, 10%) and significant BOV (CL, 46% and
V
1
, 56%). The covariate models were CL (liters/h) = 0.44 ·
e
0.0152
·
(WT
−
21
)
and
V
1
(liters) = 3.12 ·
e
0.0241
·
(WT

−

21)
, where WT is the patient's body weight (kg) centered on the study population cohort median of 21 kg. Model evaluation by the bootstrap procedure indicated that the full pharmacokinetic model was robust and parameter estimates were accurate. In conclusion, the pharmacokinetics of L-AmB in pediatric oncology patients were adequately described by the developed population model. The model has been evaluated and can be used in the design of rational dosing strategies for L-AmB antifungal therapy in this special population.
Biochemical and Molecular Characterization of Three New Variants of AmpC β-Lactamases from
Morganella morganii
Authors: Power Pablo , Galleni Moreno , Ayala Juan A. , Gutkind Gabriel 
Published: February 2006

ABSTRACT

Morganella morganii
produces an inducible, chromosomally encoded AmpC β-lactamase. We describe in this study three new variants of AmpC within this species with apparent pIs of 6.6 (M19 from
M. morganii
strain PP19), 7.4 (M29 from
M. morganii
strain PP29), and 7.8 (M37 from
M. morganii
strain PP37). After gene sequencing, deduced amino acid sequences displayed one to six substitutions when compared to the available
Morganella
AmpC sequences. An AmpR-encoding gene was also found upstream of
ampC
, including the LysR regulators' helix-turn-helix DNA-binding domain and the putative T-N
11
-A-protected region in the
ampR-ampC
intercistronic sequence. All three AmpC variants were purified from in vitro-generated derepressed mutants and showed overall similar kinetic parameters. None of the observed amino acid changes, occurring at the surface of the protein, appear to have a major influence in their catalytic properties.
Morganella
AmpCs exhibit the highest catalytic efficiencies (

k
cat

/

K
m

) on classical penicillins, cefoxitin, narrow-spectrum cephalosporins, and cefotaxime. Cefotaxime was more effectively hydrolyzed than other oxyimino-cephalosporins, whereas cefepime was 3 log-fold less efficiently hydrolyzed than other cephalosporins such as cephalothin. Several differences with other AmpC β-lactamases were found. Ampicillin was more efficiently hydrolyzed than benzylpenicillin. High

k
cat

/K
m

values were observed for oxacillin and piperacillin, which are usually poor substrates for AmpC. A fairly efficient hydrolysis of imipenem was detected as well. Aztreonam, carbenicillin, and tazobactam were effective transient inactivators of these variants.
VP35 Knockdown Inhibits Ebola Virus Amplification and Protects against Lethal Infection in Mice
Authors: Enterlein Sven , Warfield Kelly L. , Swenson Dana L. , Stein David A. , Smith Jeffery L. , Gamble C. Scott , Kroeker Andrew D. , Iversen Patrick L. , Bavari Sina , Mühlberger Elke 
Published: February 2006

ABSTRACT
Phosphorodiamidate morpholino oligomers (PMO) are a class of uncharged single-stranded DNA analogs modified such that each subunit includes a phosphorodiamidate linkage and morpholine ring. PMO antisense agents have been reported to effectively interfere with the replication of several positive-strand RNA viruses in cell culture. The filoviruses, Marburg virus and Ebola virus (EBOV), are negative-strand RNA viruses that cause up to 90% lethality in human outbreaks. There is currently no commercially available vaccine or efficacious therapeutic for any filovirus. In this study, PMO conjugated to arginine-rich cell-penetrating peptide (P-PMO) and nonconjugated PMO were assayed for the ability to inhibit EBOV infection in cell culture and in a mouse model of lethal EBOV infection. A 22-mer P-PMO designed to base pair with the translation start site region of EBOV VP35 positive-sense RNA generated sequence-specific and time- and dose-dependent inhibition of EBOV amplification in cell culture. The same oligomer provided complete protection to mice when administered before or after an otherwise lethal infection of EBOV. A corresponding nonconjugated PMO, as well as nonconjugated truncated versions of 16 and 19 base residues, provided length-dependent protection to mice when administered prophylactically. Together, these data suggest that antisense PMO and P-PMO have the potential to control EBOV infection and are promising therapeutic candidates.