bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of nelfinavir in HIV‐1‐infected pregnant and nonpregnant women
Authors: Villani P. , Floridia M. , Pirillo M. F. , Cusato M. , Tamburrini E. , Cavaliere A. F. , Guaraldi G. , Vanzini C. , Molinari A. , Antoni A. degli , Regazzi M. 
Published: April 2006

AimsTo compare steady‐state nelfinavir (NFV) pharmacokinetics in pregnant and nonpregnant HIV‐infected women.MethodsTwenty‐five pregnant HIV‐infected women were selected from an ongoing observational study evaluating the pharmacokinetics of antiretroviral agents during pregnancy. Twenty of them were in the third and five in the second trimester. Data for the control group of 21 HIV‐infected nonpregnant women were taken from a previous multicentre pharmacokinetic trial. All the participating women achieved steady‐state plasma concentrations while on a highly active antiretroviral therapy (HAART) regimen including NFV (1250 mg bid) and two nucleoside reverse transcriptase inhibitors (NRTIs). Blood samples for NFV measurement were collected predose (Ctrough) and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 h post dose.ResultsDuring the third trimester of pregnancy NFV AUC0−12 h median (range) values were 25.76 (12.61–42.74) µg h−1 ml−1, and were 32.49 (19.16–63.81) µg h−1 ml−1 in the control group [mean difference − 9.30 µg h−1 ml−1; 95% confidence interval (CI) −15.76, −2.83; P < 0.05). Median oral clearance (CL/F) was significantly higher in pregnant women than in the control group (48.5 l h−1, range 29.3–99.1 l h−1 vs. 38.5 l h−1, range 19.6–65.2 l h−1; mean difference 12.6 l h−1; 95% CI 3.3, 21.9) but the difference disappeared when CL/F was adjusted for body weight. Ctrough was significantly (P < 0.01) lower in pregnant compared with nonpregnant women (median 0.8 µg ml−1, range 0–2.6 µg ml−1 vs. 1.5 µg ml−1, range 0.5–4.9 µg ml−1; mean difference −1.0 µg ml−1; 95% CI −1.7, −0.31). The median elimination half‐life of NFV observed during pregnancy was 3.7 h (range 1.4–6.6 h), compared with 5.2 (range 3.1–10.1 h) in the control group (mean difference −1.7; 95% CI −2.8, −0.51).ConclusionsOur results indicate that women in the later stages of pregnancy may be exposed to subtherapeutic concentrations of NFV. Thus, adjustments in drug dosage or frequency of administration may be required.
Modulated microRNA expression during adult lifespan in Caenorhabditis elegans
Authors: Ibáñez‐Ventoso Carolina , Yang Maocheng , Guo Suzhen , Robins Harlan , Padgett Richard W. , Driscoll Monica 
Published: April 2006

SummaryMicroRNAs (miRNAs) are small, abundant transcripts that can bind partially homologous target messages to inhibit their translation in animal cells. miRNAs have been shown to affect a broad spectrum of biological activities, including developmental fate determination, cell signaling and oncogenesis. Little is known, however, of miRNA contributions to aging. We examined the expression of 114 identified Caenorhabditis elegans miRNAs during the adult lifespan and find that 34 miRNAs exhibit changes in expression during adulthood (P≤ 0.05), 31 with more than a twofold level change. The majority of age‐regulated miRNAs decline in relative abundance as animals grow older. Expression profiles of developmental timing regulators lin‐4 and let‐7 miRNAs, as well as conserved muscle miRNA miR‐1, show regulation during adulthood. We also used bioinformatic approaches to predict miRNA targets encoded in the C. elegans genome and we highlight candidate miRNA‐regulated genes among C. elegans genes previously shown to affect longevity, genes encoding insulin‐like ligands, and genes preferentially expressed in C. elegans muscle. Our observations identify miRNAs as potential modulators of age‐related decline and suggest a general reduction of message‐specific translational inhibition during aging, a previously undescribed feature of C. elegans aging. Since many C. elegans age‐regulated miRNAs are conserved across species, our observations identify candidate age‐regulating miRNAs in both nematodes and humans.
The microwave sky and the local Rees—Sciama effect
Authors: Rakić Aleksandar , Räsänen Syksy , Schwarz Dominik J. 
Published: April 2006

Abstract
The microwave sky shows unexpected features at the largest angular scales, among them the alignments of the dipole, quadrupole and octopole. Motivated by recent X-ray cluster studies, we investigate the possibility that local structures at the 100 h−1 Mpc scale could be responsible for such correlations. These structures give rise to a local Rees–Sciama contribution to the microwave sky that may amount to ΔT/T ∼ 10−5 at the largest angular scales. We model local structures by a spherical overdensity (Lemaître–Tolman–Bondi model) and assume that the Local Group is falling toward the centre. We superimpose the local Rees–Sciama effect on a statistically isotropic, Gaussian sky. As expected, we find alignments among low multipoles, but a closer look reveals that they do not agree with the type of correlations revealed by the data.
Polyamines Induce Resistance to Cationic Peptide, Aminoglycoside, and Quinolone Antibiotics in
Pseudomonas aeruginosa
PAO1
Authors: Kwon Dong H. , Lu Chung-Dar 
Published: April 2006

ABSTRACT

Pseudomonas aeruginosa
, a gram-negative bacterium of human pathogens, is noted for its environmental versatility, enormous metabolic capacity, and resistance to antibiotics. Overexpression of the outer membrane protein OprH and increased resistance to polycationic peptide antibiotics (e.g., polymyxin B) mediated by the PhoPQ two-component system on induction of a putative lipopolysaccharide (LPS) modification operon (
PA3552-PA3559
) have been reported as part of the adaptive responses to magnesium limitation in
P. aeruginosa
. Induction of the
oprH-phoPQ
operon and the LPS modification operon by exogenous spermidine was revealed from GeneChip analysis during studies of polyamine metabolism and was confirmed by the
lacZ
fusions of affected promoters. From the results of MIC measurements, it was found that addition of spermidine or other polyamines to the growth medium increased the MIC values of multiple antibiotics, including polycationic antibiotics, aminoglycosides, quinolones, and fluorescent dyes. MIC values of these compounds in the transposon insertion mutants of
oprH
,
phoP
,
phoQ
, and
pmrB
were also determined in the presence and absence of spermidine. The results showed that the spermidine effect on cationic peptide antibiotic and quinolone resistance was diminished in the
phoP
mutant only. The spermidine effect on antibiotics was not influenced by magnesium concentrations, as demonstrated by MICs and
oprH
::
lacZ
fusion studies in the presence of 20 μM or 2 mM magnesium. Furthermore, in spermidine uptake mutants, MICs of cationic peptide antibiotics and fluorescent dyes, but not of aminoglycosides and quinolones, were increased by spermidine. These results suggested the presence of a complicated molecular mechanism for polyamine-mediated resistance to multiple antibiotics in
P. aeruginosa
.
Randomized, Double-Blind Study of Emtricitabine (FTC) plus Clevudine versus FTC Alone in Treatment of Chronic Hepatitis B
Authors: Lim Seng Gee , Krastev Zahary , Ng Tay Meng , Mechkov Grigor , Kotzev Iskren Andreev , Chan Sing , Mondou Elsa , Snow Andrea , Sorbel Jeff , Rousseau Franck 
Published: April 2006

ABSTRACT

Emtricitabine (FTC) is approved for the treatment of human immunodeficiency virus. FTC and clevudine (CLV) have activity against hepatitis B virus (HBV). This report summarizes the results of a double-blind, multicenter study of patients with chronic hepatitis B who had completed a phase 3 study of FTC and were randomized 1:1 to 200 mg FTC once daily (QD) plus 10 mg CLV QD or 200 mg FTC QD plus placebo for 24 weeks with 24 weeks of follow-up. One hundred sixty-three patients were treated (82 with FTC plus CLV [FTC+CLV] and 81 with FTC); 72% were men, 53% were Asian, 47% were Caucasian, and 52% were hepatitis B e antigen positive, and the median baseline HBV DNA level was 6 log
10
copies/ml. After 24 weeks of treatment, 74% (FTC+CLV) versus 65% (FTC alone) had serum HBV DNA levels of <4,700 copies/ml (
P
= 0.114) (Digene HBV Hybrid Capture II assay). Twenty-four weeks posttreatment, the mean change in serum HBV DNA levels from baseline was −1.25 log
10
copies/ml (FTC+CLV), 40% had undetectable viremia (versus 23% for FTC alone), and 63% had normal alanine aminotransferase levels (versus 42% for FTC alone) (
P
≤ 0.025 for all endpoints). The safety profile was similar between arms during treatment, with less posttreatment exacerbation of hepatitis B in the combination arm. In summary, after 24 weeks of treatment, no significant difference between arms was observed, but there was a significantly greater virologic and biochemical response 24 weeks posttreatment in the FTC+CLV arm.
New Potential Antimalarial Agents: Therapeutic-Index Evaluation of Pyrroloquinazolinediamine and Its Prodrugs in a Rat Model of Severe Malaria
Authors: Xie Lisa H. , Li Qigui , Lin Ai J. , Smith Kirsten , Zhang Jing , Skillman Donald S. 
Published: April 2006

ABSTRACT

Tetra-acetamide pyrroloquinazolinediamine (PQD-A4) and bis-ethylcarbamyl pyrroloquinazolinediamine (PQD-BE) are new derivatives of pyrroloquinazolinediamine (PQD) and are being investigated as potential chemotherapeutic agents for the treatment of malaria. Comparative studies to assess the therapeutic indices of PQD-A4, PQD-BE, and PQD were conducted in
Plasmodium berghei
-infected rats following daily intragastric dosing for three consecutive days. Artesunate (AS), a standard drug for treatment of severe malaria, was used as a comparator. The minimum doses required to clear malaria parasitemia were 156 μmol/kg of body weight for AS and 2.4 μmol/kg for PQD, PQD-4A, and PQD-BE. The maximum tolerated dose (MTD) of AS was 625 μmol/kg, and its therapeutic index was calculated to be 4. The MTDs of PQD-A4, PQD-BE, and PQD were found to be 190, 77, and 24 μmol/kg, respectively, yielding therapeutic indices of 80, 32, and 10, respectively. Although PQD-A4 and PQD-BE are only half as potent as PQD based on their curative effects, the two new derivatives, PQD-4A and PQD-BE, are 8.0-fold and 3.2-fold safer, respectively, than their parent compound when they are dosed for three consecutive days. Oral PQD-A4 and PQD-BE are 44 to 70 times more potent on an mg basis than intravenous AS. As assessed from the therapeutic index over 3 days, PQD-A4, PQD-BE, and PQD administered orally are 20.0, 8.0, and 2.5 times safer than AS given intravenously. The results indicate that PQD-4A is a promising candidate for antimalarial treatment.
Pharmacokinetics of Telbivudine in Subjects with Various Degrees of Hepatic Impairment
Authors: Zhou Xiao-Jian , Marbury Thomas C. , Alcorn Harry W. , Smith William B. , Dubuc Patrick Gloria , Chao George C. , Brown Nathaniel A. 
Published: April 2006

ABSTRACT
This study evaluated the effect of hepatic impairment on the pharmacokinetics of telbivudine, an investigational nucleoside antiviral for the treatment of chronic hepatitis B virus infection. Twenty-four subjects were assigned to four hepatic function groups (normal function and mild, moderate, and severe impairment, with six subjects in each group) on the basis of Child-Pugh scores. The subjects were administered a single oral dose of 600 mg telbivudine, and blood samples were collected over a 48-h interval for pharmacokinetic analyses. Telbivudine was well tolerated by all subjects. Telbivudine plasma concentration-time profiles were similar across the four hepatic function groups. The principal pharmacokinetic parameters of drug exposure, i.e., the maximum plasma concentration and area under the drug concentration-time curve, were comparable between subjects with various degrees of hepatic impairment and those with normal hepatic function. Results from this single-dose pharmacokinetic assessment therefore provide a pharmacologic rationale for further evaluation of the safety and efficacy of telbivudine in hepatitis B virus-infected patients with decompensated liver diseases.
Activity of Retapamulin against
Streptococcus pyogenes
and
Staphylococcus aureus
Evaluated by Agar Dilution, Microdilution, E-Test, and Disk Diffusion Methodologies
Authors: Pankuch Glenn A. , Lin Gengrong , Hoellman Dianne B. , Good Caryn E. , Jacobs Michael R. , Appelbaum Peter C. 
Published: April 2006

ABSTRACT

The in vitro activity of retapamulin against 106
Staphylococcus aureus
isolates and 109
Streptococcus pyogenes
isolates was evaluated by the agar dilution, broth microdilution, E-test, and disk diffusion methodologies. Where possible, the tests were performed by using the CLSI methodology. The results of agar dilution, broth microdilution, and E-test (all with incubation in ambient air) for
S. aureus
yielded similar MICs, in the range of 0.03 to 0.25 μg/ml. These values corresponded to zone diameters between 25 and 33 mm by the use of a 2-μg retapamulin disk. Overall, 99% of the agar dilution results and 95% of E-test results for
S. aureus
were within ±1 dilution of the microdilution results. For
S. pyogenes
, the MICs obtained by the agar and broth microdilution methods (both after incubation in ambient air) were in the range of 0.008 to 0.03 μg/ml, and E-test MICs (with incubation in ambient air) were 0.016 to 0.06 μg/ml. For
S. pyogenes
, 100% of the agar dilution MIC results were within ±1 dilution of the broth microdilution results. E-test MICs (after incubation in ambient air) were within ±1 and ±2 dilutions of the broth microdilution results for 76% and 99% of the isolates, respectively. E-test MICs for
S. pyogenes
strains in CO
2
were up to 4 dilutions higher than those in ambient air. Therefore, it is recommended that when retapamulin MICs are determined by E-test, incubation be done in ambient air and not in CO
2
, due to the adverse effect of CO
2
on the activity of this compound. Diffusion zones (with incubation in CO
2
) for
S. pyogenes
were 18 to 24 mm. Retapamulin MICs for all strains by all methods (with incubation in ambient air) were ≤0.25 μg/ml. These results demonstrate that
S. pyogenes
(including macrolide-resistant strains) and
S. aureus
(including methicillin-resistant and vancomycin-nonsusceptible strains) are inhibited by very low concentrations of retapamulin and that all four testing methods are satisfactory for use for susceptibility testing.
Antimalarial Activity of Allicin, a Biologically Active Compound from Garlic Cloves
Authors: Coppi Alida , Cabinian Melissa , Mirelman David , Sinnis Photini 
Published: April 2006

ABSTRACTThe incidence of malaria is increasing, and there is an urgent need to identify new drug targets for both prophylaxis and chemotherapy. Potential new drug targets includePlasmodiumproteases that play critical roles in the parasite life cycle. We have previously shown that the major surface protein ofPlasmodiumsporozoites, the circumsporozoite protein (CSP), is proteolytically processed by a parasite-derived cysteine protease, and this processing event is temporally associated with sporozoite invasion of host cells. E-64, a cysteine protease inhibitor, inhibits CSP processing and prevents invasion of host cells in vitro and in vivo. Here we tested allicin, a cysteine protease inhibitor found in garlic extracts, for its ability to inhibit malaria infection. At low concentrations, allicin was not toxic to either sporozoites or mammalian cells. At these concentrations, allicin inhibited CSP processing and prevented sporozoite invasion of host cells in vitro. In vivo, mice injected with allicin had decreasedPlasmodiuminfections compared to controls. When sporozoites were treated with allicin before injection into mice, malaria infection was completely prevented. We also tested allicin on erythrocytic stages and found that a 4-day regimen of allicin administered either orally or intravenously significantly decreased parasitemias and increased the survival of infected mice by 10 days. Together, these experiments demonstrate that the same cysteine protease inhibitor can target two different life cycle stages in the vertebrate host.
Clarithromycin Delays Progression of Bronchial Epithelial Cells from G
1
Phase to S Phase and Delays Cell Growth via Extracellular Signal-Regulated Protein Kinase Suppression
Authors: Shinkai Masaharu , Tamaoki Jun , Kobayashi Hideo , Kanoh Soichiro , Motoyoshi Kazuo , Kute Tim , Rubin Bruce K. 
Published: April 2006

ABSTRACT

The nonsteroidal anti-inflammatory drugs have been shown to support cytoprotection of cells by shifting cells toward a quiescent state (G
0
/G
1
). Extracellular signal-regulated kinase (ERK) is required for cells to pass from G
1
phase into S phase, and macrolide antibiotics can inhibit ERK1/2 phosphorylation. However, previous reports suggest that macrolide antibiotics do not affect cell growth in bronchial epithelial cells. Therefore, we studied normal human bronchial epithelial (NHBE) cells to determine whether clarithromycin (CAM) suppresses ERK, delays bronchial epithelial cells from progressing to S phase, and delays cell growth. Exposure to CAM at 10 μg/ml daily over 4 days irreversibly decreased the cell proliferation with and without growth supplements (
P
< 0.0001). CAM also inhibited ERK1/2 phosphorylation over the first 90 min of exposure (
P
< 0.05 for 30 min,
P
< 0.0001 for 60 min, and
P
< 0.01 for 90 min) and decreased the ratio of phosphorylated ERK1/2 (pERK1/2) to total ERK1/2 (tERK1/2) (
P
< 0.0001). Incubation with CAM for 48 h increased the proportion of cells in G
1
phase (means ± standard deviations) from 63.5% ± 0.9% to 79.1% ± 1.4% (
P
< 0.0001), decreased that in S phase from 19.8% ± 1.2% to 10.0% ± 2.1% (
P
< 0.01), and decreased that in G
2
/M phase from 16.7% ± 0.4% to 11.0% ± 0.8% (
P
< 0.001). In contrast, the ratio of pMEK1/2 to tMEK1/2 was not altered after exposure to CAM. These results suggest that macrolide antibiotics can delay the progression of NHBE cells from G
1
phase to S phase and can slow cell growth, probably through the suppression of ERK1/2.
Complex Genetic Structures with Repeated Elements, a
sul
-Type Class 1 Integron, and the
bla
VEB
Extended-Spectrum β-Lactamase Gene
Authors: Naas Thierry , Aubert Daniel , Lambert Thierry , Nordmann Patrice 
Published: April 2006

ABSTRACT

Two clinical isolates of
Pseudomonas aeruginosa
, TL-1 and TL-2, were isolated from a patient transferred from Bangladesh and hospitalized for osteomyelitis in Paris, France.
P. aeruginosa
TL-1 expressed the extended-spectrum β-lactamase VEB-1a and was susceptible only to imipenem and colistin, while
P. aeruginosa
TL-2 expressed only the naturally occurring
bla
AmpC
gene at a basal level and exhibited a wild-type β-lactam resistance phenotype. In TL-1, the typical 5′-end conserved sequence (5′-CS) region of class 1 integrons usually present upstream of the
bla
VEB-1a
gene was replaced by a truncated 3′-CS and a 135-bp repeated element (Re). Downstream of the
bla
VEB-1a
gene, an insertion sequence, IS
Pa31
disrupted by IS
Pa30
, and an
orf513
sequence, belonging to a common region (conserved region 1 [CR1]) immediately upstream of the
aphA-6
gene, were present. Further downstream, a second truncated 3′-CS region in direct repeat belonged to In51, an integron containing two gene cassettes (
aadA6
and the OrfD cassette). Thus, the overall structure corresponded to a
sul
-type class 1 integron termed In121. Genetic analyses revealed that both isolates were clonally related and differed by a ca. 100-kb fragment that contained In121. Both isolates contained another integron, In122, that carried three gene cassettes:
aadB
,
dfrA1
, and the OrfX cassette. This work identifies for the first time the spread of Re-associated
bla
VEB
genes located on a
sul
-type integron. It also reports for the first time a CR1 element in
P. aeruginosa
that is associated with an aminoglycoside resistance
aphA-6
gene that is expressed from a composite promoter.
Poly(I)-Poly(C
12
U) but Not Ribavirin Prevents Death in a Hamster Model of Nipah Virus Infection
Authors: Georges-Courbot M. C. , Contamin H. , Faure C. , Loth P. , Baize S. , Leyssen P. , Neyts J. , Deubel V. 
Published: April 2006

ABSTRACT

Clinical nonrandomized trials demonstrate some efficacy for ribavirin in the treatment of patients with severe Nipah virus-induced encephalitis. We report here that EICAR, the 5-ethynyl analogue of ribavirin, and the OMP-decarboxylase inhibitors 6-aza-uridine and pyrazofurin have strong antiviral activity against Nipah virus replication in vitro. Ribavirin and 6-aza-uridine were tested further in hamsters infected with a lethal dose of Nipah virus. The activity of these small-molecule inhibitors was compared with that of the interferon inducer poly(I)-poly(C
12
U). Both ribavirin and 6-aza-uridine were able to delay but not prevent Nipah virus-induced mortality. Poly(I)-poly(C
12
U), at 3 mg/kg of body weight daily from the day of infection to 10 days postinfection, prevented mortality in 5 of 6 infected animals.
Stepwise Upregulation of thePseudomonas aeruginosaChromosomal Cephalosporinase Conferring High-Level β-Lactam Resistance Involves Three AmpD Homologues
Authors: Juan Carlos , Moyá Bartolomé , Pérez José L. , Oliver Antonio 
Published: April 2006

ABSTRACTDevelopment of resistance to the antipseudomonal penicillins and cephalosporins mediated by hyperproduction of the chromosomal cephalosporinase AmpC is a major threat to the successful treatment ofPseudomonas aeruginosainfections. AlthoughampDinactivation has been previously found to lead to a partially derepressed phenotype characterized by increased AmpC production but retaining further inducibility, the regulation ofampCinP. aeruginosais far from well understood. We demonstrate thatampCexpression is coordinately repressed by three AmpD homologues, including the previously described protein AmpD plus two additional proteins, designated AmpDh2 and AmpDh3. The three AmpD homologues are responsible for a stepwiseampCupregulation mechanism ultimately leading to constitutive hyperexpression of the chromosomal cephalosporinase and high-level antipseudomonal β-lactam resistance, as shown by analysis of the three singleampDmutants, the three doubleampDmutants, and the tripleampDmutant. This is achieved by a three-step escalating mechanism rendering four relevant expression states: basal-level inducible expression (wild type), moderate-level hyperinducible expression with increased antipseudomonal β-lactam resistance (ampDmutant), high-level hyperinducible expression with high-level β-lactam resistance (ampD ampDh3double mutant), and very high-level (more than 1,000-fold compared to the wild type) derepressed expression (triple mutant). Although one-step inducible-derepressed expression models are frequent in natural resistance mechanisms, this is the first characterized example in which expression of a resistance gene can be sequentially amplified through multiple steps of derepression.