bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of the Hepatitis C Virus Protease Inhibitor Faldaprevir on the Pharmacokinetics of an Oral Contraceptive Containing Ethinylestradiol and Levonorgestrel in Healthy Female Volunteers
Authors: Sabo John P. , Lang Benjamin , Elgadi Mabrouk , Huang Fenglei 
Published: November 2014

ABSTRACT

Faldaprevir is a potent hepatitis C virus (HCV) NS3/4A protease inhibitor. Faldaprevir is known to inhibit P-glycoprotein, CYP3A4, and UDP-glucuronosyltransferase 1A1. This study evaluated the effect of steady-state 240 mg faldaprevir on the pharmacokinetics (PK) of an oral contraceptive containing ethinylestradiol (EE) and levonorgestrel (LNG) in healthy premenopausal women. In period 1, subjects received EE/LNG once daily (QD) for 14 days. Blood samples were taken on days 1, 11, and 12, with intensive PK blood sampling for EE and LNG on day 13. In period 2, subjects received EE-LNG QD and 240 mg faldaprevir QD on days 14 to 21 (240 mg faldaprevir twice daily on day 14). Blood samples were taken on days 14, 19, and 20, with PK profiling samples obtained for EE and LNG on day 21. A total of 15/16 subjects completed the study. Overall, EE and LNG exposure (assessed by the area under the curve) was approximately 1.4-fold higher when EE and LNG were coadministered with faldaprevir than when administered alone. Median
t
1/2
(terminal half-life in plasma at steady state) values were prolonged for both EE (2.4 h longer) and LNG (4.7 h longer) when EE and LNG were coadministered with faldaprevir. The mean oral clearance and apparent volume of distribution of both EE and LNG were lower (∼30%) when EE and LNG were coadministered with faldaprevir. Coadministration of faldaprevir and an oral contraceptive resulted in a moderate increase in exposure to both EE and LNG. However, this increase was not considered clinically meaningful, and no dose adjustment of oral contraceptives was deemed necessary. (This study has been registered at ClinicalTrials.gov under registration number NCT01570244.)
Pharmacokinetic Interactions between Primaquine and Pyronaridine-Artesunate in Healthy Adult Thai Subjects
Authors: Jittamala Podjanee , Pukrittayakamee Sasithon , Ashley Elizabeth A. , Nosten François , Hanboonkunupakarn Borimas , Lee Sue J. , Thana Praiya , Chairat Kalayanee , Blessborn Daniel , Panapipat Salwaluk , White Nicholas J. , Day Nicholas P. J. , Tarning Joel 
Published: November 2014

ABSTRACT
Pyronaridine-artesunate is a newly introduced artemisinin-based combination treatment which may be deployed together with primaquine. A single-dose, randomized, three-sequence crossover study was conducted in healthy Thai volunteers to characterize potential pharmacokinetic interactions between these drugs. Seventeen healthy adults received a single oral dose of primaquine alone (30 mg base) and were then randomized to receive pyronaridine-artesunate alone (540−180 mg) or pyronaridine-artesunate plus primaquine in combination, with intervening washout periods between all treatments. The pharmacokinetic properties of primaquine, its metabolite carboxyprimaquine, artesunate, its metabolite dihydroartemisinin, and pyronaridine were assessed in 15 subjects using a noncompartmental approach followed by a bioequivalence evaluation. All drugs were well tolerated. The single oral dose of primaquine did not result in any clinically relevant pharmacokinetic alterations to pyronaridine, artesunate, or dihydroartemisinin exposures. There were significantly higher primaquine maximum plasma drug concentrations (geometric mean ratio, 30%; 90% confidence interval [CI], 17% to 46%) and total exposures (15%; 6.4% to 24%) during coadministration with pyronaridine-artesunate than when primaquine was given alone. Pyronaridine, like chloroquine and piperaquine, increases plasma primaquine concentrations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01552330.)
Lycopene Attenuates Colistin-Induced Nephrotoxicity in Mice via Activation of the Nrf2/HO-1 Pathway
Authors: Dai Chongshan , Tang Shusheng , Deng Sijun , Zhang Shen , Zhou Yan , Velkov Tony , Li Jian , Xiao Xilong 
Published: November 2014

ABSTRACT

Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (
P
< 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both
P
< 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.
Lead Clinical and Preclinical Antimalarial Drugs Can Significantly Reduce Sporozoite Transmission to Vertebrate Populations
Authors: Upton L. M. , Brock P. M. , Churcher T. S. , Ghani A. C. , Gething P. W. , Delves M. J. , Sala K. A. , Leroy D. , Sinden R. E. , Blagborough A. M. 
Published: November 2014

ABSTRACT

To achieve malarial elimination, we must employ interventions that reduce the exposure of human populations to infectious mosquitoes. To this end, numerous antimalarial drugs are under assessment in a variety of transmission-blocking assays which fail to measure the single crucial criteria of a successful intervention, namely impact on case incidence within a vertebrate population (reduction in reproductive number/effect size). Consequently, any reduction in new infections due to drug treatment (and how this may be influenced by differing transmission settings) is not currently examined, limiting the translation of any findings. We describe the use of a laboratory population model to assess how individual antimalarial drugs can impact the number of secondary
Plasmodium berghei
infections over a cycle of transmission. We examine the impact of multiple clinical and preclinical drugs on both insect and vertebrate populations at multiple transmission settings. Both primaquine (>6 mg/kg of body weight) and NITD609 (8.1 mg/kg) have significant impacts across multiple transmission settings, but artemether and lumefantrine (57 and 11.8 mg/kg), OZ439 (6.5 mg/kg), and primaquine (<1.25 mg/kg) demonstrated potent efficacy only at lower-transmission settings. While directly demonstrating the impact of antimalarial drug treatment on vertebrate populations, we additionally calculate effect size for each treatment, allowing for head-to-head comparison of the potential impact of individual drugs within epidemiologically relevant settings, supporting their usage within elimination campaigns.
Lack of Neuropathological Changes in Rats Administered Tedizolid Phosphate for Nine Months
Authors: Schlosser Michael J. , Hosako Hiromi , Radovsky Ann , Butt Mark T. , Draganov Dragomir , Vija Jenifer , Oleson Frederick 
Published: November 2014

ABSTRACT
Tedizolid, a novel oxazolidinone antibacterial, was administered to Long Evans rats by oral gavage once daily for up to 9 months at doses near the maximum tolerated dose (MTD) to evaluate for potential neurotoxicity. Mean plasma exposures of tedizolid at the low-, medium-, and high-dose levels (7.5, 15, and 30 mg/kg of body weight/day for males; 2.5, 5, and 10 mg/kg/day for females) were similar between males and females and were 1.8-, 3.9-, and 8.0-fold greater than exposures in patients at the therapeutic dose (200 mg once daily). Evaluated endpoints included survival, clinical observations, body weight, and food consumption. At 1, 3, 6, and 9 months, ophthalmic examinations, functional observational batteries, and locomotor activity measures were conducted, brain weights/sizes were recorded, and perfusion-fixed tissues were collected from 12 rats/sex/group/time point. A detailed morphological assessment was conducted on brain, eyes, optic nerve/tract, spinal cord, peripheral nerves (includes sciatic, sural, tibial, peroneal, trigeminal), and skeletal muscle. At the end of 9 months, less body weight gain was seen in high-dose males (−6.7%) and females (−5.8%) compared with that seen in controls. There were no tedizolid-related adverse neurobehavioral effects or tedizolid-related histopathologic changes in the central/peripheral nervous systems, including the optic nerve. Results of this study indicate that tedizolid was not neurotoxic when administered long term to pigmented rats at doses near the MTD, which were up to 8-fold higher than the human therapeutic exposure.
Genomic and Transcriptomic Analyses of Colistin-Resistant Clinical Isolates of Klebsiella pneumoniae Reveal Multiple Pathways of Resistance
Authors: Wright Meredith S. , Suzuki Yo , Jones Marcus B. , Marshall Steven H. , Rudin Susan D. , van Duin David , Kaye Keith , Jacobs Michael R. , Bonomo Robert A. , Adams Mark D. 
Published: November 2014

ABSTRACT

The emergence of multidrug-resistant (MDR)
Klebsiella pneumoniae
has resulted in a more frequent reliance on treatment using colistin. However, resistance to colistin (Col
r
) is increasingly reported from clinical settings. The genetic mechanisms that lead to Col
r
in
K. pneumoniae
are not fully characterized. Using a combination of genome sequencing and transcriptional profiling by RNA sequencing (RNA-Seq) analysis, distinct genetic mechanisms were found among nine Col
r
clinical isolates. Col
r
was related to mutations in three different genes in
K. pneumoniae
strains, with distinct impacts on gene expression. Upregulation of the
pmrH
operon encoding 4-amino-4-deoxy-
l
-arabinose (Ara4N) modification of lipid A was found in all Col
r
strains. Alteration of the
mgrB
gene was observed in six strains. One strain had a mutation in
phoQ
. Common among these seven strains was elevated expression of
phoPQ
and unaltered expression of
pmrCAB
, which is involved in phosphoethanolamine addition to lipopolysaccharide (LPS). In two strains, separate mutations were found in a previously uncharacterized histidine kinase gene that is part of a two-component regulatory system (TCRS) now designated
crrAB
. In these strains, expression of
pmrCAB
,
crrAB
, and an adjacent glycosyltransferase gene, but not that of
phoPQ
, was elevated. Complementation with the wild-type allele restored colistin susceptibility in both strains. The
crrAB
genes are present in most
K. pneumoniae
genomes, but not in
Escherichia coli
. Additional upregulated genes in all strains include those involved in cation transport and maintenance of membrane integrity. Because the
crrAB
genes are present in only some strains, Col
r
mechanisms may be dependent on the genetic background.
In Vitro
Antibacterial Activity of AZD0914, a New Spiropyrimidinetrione DNA Gyrase/Topoisomerase Inhibitor with Potent Activity against Gram-Positive, Fastidious Gram-Negative, and Atypical Bacteria
Authors: Huband Michael D. , Bradford Patricia A. , Otterson Linda G. , Basarab Gregory S. , Kutschke Amy C. , Giacobbe Robert A. , Patey Sara A. , Alm Richard A. , Johnstone Michele R. , Potter Marie E. , Miller Paul F. , Mueller John P. 
Published: November 2014

ABSTRACT

AZD0914 is a new spiropyrimidinetrione bacterial DNA gyrase/topoisomerase inhibitor with potent
in vitro
antibacterial activity against key Gram-positive (
Staphylococcus aureus
,
Staphylococcus epidermidis
,
Streptococcus pneumoniae
,
Streptococcus pyogenes
, and
Streptococcus agalactiae
), fastidious Gram-negative (
Haemophilus influenzae
and
Neisseria gonorrhoeae
), atypical (
Legionella pneumophila
), and anaerobic (
Clostridium difficile
) bacterial species, including isolates with known resistance to fluoroquinolones. AZD0914 works via inhibition of DNA biosynthesis and accumulation of double-strand cleavages; this mechanism of inhibition differs from those of other marketed antibacterial compounds. AZD0914 stabilizes and arrests the cleaved covalent complex of gyrase with double-strand broken DNA under permissive conditions and thus blocks religation of the double-strand cleaved DNA to form fused circular DNA. Whereas this mechanism is similar to that seen with fluoroquinolones, it is mechanistically distinct. AZD0914 exhibited low frequencies of spontaneous resistance in
S. aureus
, and if mutants were obtained, the mutations mapped to
gyrB
. Additionally, no cross-resistance was observed for AZD0914 against recent bacterial clinical isolates demonstrating resistance to fluoroquinolones or other drug classes, including macrolides, β-lactams, glycopeptides, and oxazolidinones. AZD0914 was bactericidal in both minimum bactericidal concentration and
in vitro
time-kill studies. In
in vitro
checkerboard/synergy testing with 17 comparator antibacterials, only additivity/indifference was observed. The potent
in vitro
antibacterial activity (including activity against fluoroquinolone-resistant isolates), low frequency of resistance, lack of cross-resistance, and bactericidal activity of AZD0914 support its continued development.
Antibody Response Specific to the Capsular Polysaccharide Is Impaired in Streptococcus suis Serotype 2-Infected Animals
Authors: Calzas Cynthia , Lemire Paul , Auray Gael , Gerdts Volker , Gottschalk Marcelo , Segura Mariela 
Published: November 2014

ABSTRACT

Streptococcus suis
serotype 2 is an extracellular encapsulated bacterium that causes severe septicemia and meningitis in swine and humans. Albeit crucial in the fight against encapsulated bacteria, the nature of the capsular polysaccharide (CPS)-specific antibody (Ab) response during
S. suis
type 2 infection is unknown. We compared for the first time the features of CPS-specific versus protein-specific Ab responses during experimental infections with live virulent
S. suis
type 2 in mice. The primary protein-specific Ab response was dominated by both type 1 and 2 IgG subclasses, whereas IgM titers were more modest. The secondary protein-specific Ab response showed all of the features of a memory response with faster kinetics and boosted the titers of all Ig isotypes. In contrast, the primary CPS-specific Ab response was either inexistent or had titers only slightly higher than those in noninfected animals and was essentially composed of IgM. A poor CPS-specific memory response was observed, with only a moderate boost in IgM titers and no IgG. Both protein- and CPS-specific Ab responses were Toll-like receptor 2 independent. By using
S. suis
type 2 strains of European or North American origin, the poor CPS-specific Ab response was demonstrated to be independent of the genotypic/phenotypic diversity of the strain within serotype 2. Finally, the CPS-specific Ab response was also impaired and lacked isotype switching in
S. suis
-infected pigs, the natural host of the bacterium. The better resistance of preinfected animals to reinfection with the same strain of
S. suis
type 2 might thus more likely be related to the development of a protein rather than CPS Ab response.
Role of Dendritic Cells in the Pathogenesis of Whipple's Disease
Authors: Schinnerling Katina , Geelhaar-Karsch Anika , Allers Kristina , Friebel Julian , Conrad Kristina , Loddenkemper Christoph , Kühl Anja A. , Erben Ulrike , Ignatius Ralf , Moos Verena , Schneider Thomas 
Published: November 2014

ABSTRACT

Accumulation of
Tropheryma whipplei
-stuffed macrophages in the duodenum, impaired
T. whipplei
-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC
ex vivo
or after
in vitro
maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry
in situ
. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c
high
myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype.
In vitro
-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate
T. whipplei
-specific Th1 cells. In duodenal and lymphoid tissues,
T. whipplei
was found within immature DC-SIGN
+
DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of
T. whipplei
-specific T cells during CWD and that immature DC carrying
T. whipplei
contribute to the dissemination of the bacterium.
The Polyamine
N
-Acetyltransferase-Like Enzyme PmvE Plays a Role in the Virulence of Enterococcus faecalis
Authors: Martini Cecilia , Michaux Charlotte , Bugli Francesca , Arcovito Alessandro , Iavarone Federica , Cacaci Margherita , Sterbini Francesco Paroni , Hartke Axel , Sauvageot Nicolas , Sanguinetti Maurizio , Posteraro Brunella , Giard Jean-Christophe 
Published: November 2014

ABSTRACT

We previously showed that the mutant strain of
Enterococcus faecalis
lacking the transcriptional regulator SlyA is more virulent than the parental strain. We hypothesized that this phenotype was due to overexpression of the second gene of the
slyA
operon,
ef_3001
, renamed
pmvE
(for
p
olyamine
m
etabolism and
v
irulence of
E. faecalis
). PmvE shares strong homologies with
N

1

-spermidine/spermine acetyltransferase enzymes involved in the metabolism of polyamines. In this study, we used an
E. faecalis
strain carrying the recombinant plasmid pMSP3535-
pmvE
(V19/p3535-
pmvE
), which allows the induction of
pmvE
by addition of nisin. Thereby, we showed that the overexpression of PmvE increased the virulence of
E. faecalis
in the
Galleria mellonella
infection model, as well as the persistence within peritoneal macrophages. We were also able to show a direct interaction between the His-tagged recombinant PmvE (rPmvE) protein and putrescine by the surface plasmon resonance (SPR) technique on a Biacore instrument. Moreover, biochemical assays showed that PmvE possesses an
N
-acetyltransferase activity toward polyamine substrates. Our results suggest that PmvE contributes to the virulence of
E. faecalis
, likely through its involvement in the polyamine metabolism.
Pseudomonas aeruginosa LysR PA4203 Regulator NmoR Acts as a Repressor of the PA4202
nmoA
Gene, Encoding a Nitronate Monooxygenase
Authors: Vercammen Ken , Wei Qing , Charlier Daniel , Dötsch Andreas , Haüssler Susanne , Schulz Sebastian , Salvi Francesca , Gadda Giovanni , Spain Jim , Rybtke Morten Levin , Tolker-Nielsen Tim , Dingemans Jozef , Ye Lumeng , Cornelis Pierre 
Published: November 2014

ABSTRACT

The PA4203 gene encodes a LysR regulator and lies between the
ppgL
gene (PA4204), which encodes a periplasmic gluconolactonase, and, in the opposite orientation, the PA4202 (
nmoA
) gene, coding for a nitronate monooxygenase, and
ddlA
(PA4201), encoding a
d
-alanine alanine ligase. The intergenic regions between PA4203 and
ppgL
and between PA4203 and
nmoA
are very short (79 and 107 nucleotides, respectively). Here we show that PA4203 (
nmoR
) represses its own transcription and the expression of
nmoA
. A chromatin immunoprecipitation analysis showed the presence of a single NmoR binding site between
nmoA
and
nmoR
, which was confirmed by electrophoretic mobility shift assays (EMSAs) with the purified NmoR protein. Despite this observation, a transcriptome analysis revealed more genes to be affected in an
nmoR
mutant, including genes known to be part of the MexT LysR activator regulon. The PA1225 gene, encoding a quinone oxidoreductase, was the most highly upregulated gene in the
nmoR
deletion mutant, independently of MexT. Finally, deletion of the
nmoA
gene resulted in an increased sensitivity of the cells to 3-nitropropionic acid (3-NPA), confirming the role of the nitronate monooxygenase protein in the detoxification of nitronate.
Depression, adherence and attrition from care in HIV-infected adults receiving antiretroviral therapy
Authors: Krumme Alexis A , Kaigamba Felix , Binagwaho Agnes , Murray Megan B , Rich Michael L , Franke Molly F 
Published: November 2014

BackgroundA better understanding of the relationship between depression and HIV-related outcomes, particularly as it relates to adherence to treatment, is critical to guide effective support and treatment of individuals with HIV and depression. We examined whether depression was associated with attrition from care in a cohort of 610 HIV-infected adults in rural Rwanda and whether this relationship was mediated through suboptimal adherence to treatment.MethodsThe association between depression and attrition from care was evaluated with a Cox proportional hazard model and with mediation methods that calculate the direct and indirect effects of depression on attrition and are able to account for interactions between depression and suboptimal adherence. Depression was assessed with the Hopkins Symptom Checklist-15; attrition was defined as death, treatment default, or loss to follow-up.ResultsBaseline depression was significantly associated with time to attrition after adjustment for receipt of community-based accompaniment, physical functioning quality of life score, and CD4 cell count (HR=2.40, 95% CI 1.27 to 4.52, p=0.005). In multivariable mediation analysis, we found no evidence that the association between depression and attrition after 3 months was mediated by suboptimal adherence (direct effect of depression on attrition: OR=3.90 (1.26 to 12.04), p=0.02; indirect effect: OR=1.07 (0.92 to 1.25), p=0.38).ConclusionsEven in the context of high antiretroviral therapy adherence, depression may adversely influence HIV outcomes through a pathway other than suboptimal adherence. Treatment of depression is critical to achieving good mental health and retention in HIV-infected individuals with depression.