bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients
Authors: Moltó José , Valle Marta , Miranda Cristina , Cedeño Samandhy , Negredo Eugenia , Clotet Bonaventura 
Published: March 2012

ABSTRACTThe aim of this open-label, fixed-sequence study was to investigate the potential of the botanical supplement milk thistle (silymarin) to interact with the boosted protease inhibitor combination darunavir-ritonavir. Fifteen HIV-infected patients receiving antiretroviral therapy with darunavir-ritonavir (600/100 mg twice daily) for at least 4 weeks were included. Silymarin (150 mg every 8 h) was added to the antiretroviral treatment from days 1 to 14. Darunavir concentrations in plasma were determined by high-performance liquid chromatography immediately before and 1, 2, 4, 6, 8, 10, and 12 h after a morning dose of darunavir-ritonavir on day 0 and darunavir-ritonavir plus silymarin on day 14. Individual darunavir pharmacokinetic parameters were calculated by noncompartmental analysis and compared between days 0 and 14 by means of the geometric mean ratio (GMR) and its 90% confidence interval (CI). The median age was 48 years (interquartile range, 44 to 50 years), and the median body weight was 70 kg (interquartile range, 65 to 84 kg). Silymarin was well tolerated, and all participants completed the study. The GMRs for darunavir coadministered with silymarin relative to darunavir alone were 0.86 (90% CI, 0.70 to 1.05) for the area under the concentration-time curve from 0 to 12 h, 0.83 (90% CI, 0.80 to 0.98) for the maximum concentration, and 0.94 (90% CI, 0.73 to 1.19) for the concentration at the end of the dosing interval. In summary, coadministration of silymarin with darunavir-ritonavir seems to be safe in HIV-infected patients; no dose adjustment for darunavir-ritonavir seems to be necessary.
Activity of Oxacillin versus That of Vancomycin against Oxacillin-Susceptible
mecA
-Positive Staphylococcus aureus Clinical Isolates Evaluated by Population Analyses, Time-Kill Assays, and a Murine Thigh Infection Model
Authors: Labrou Maria , Michail George , Ntokou Eleni , Pittaras Theodore E. , Pournaras Spyros , Tsakris Athanassios 
Published: March 2012

ABSTRACT

We compared the activity of dicloxacillin with that of vancomycin against 15 oxacillin-susceptible, methicillin-resistant
Staphylococcus aureus
(OS-MRSA) clinical isolates. By population analyses, we found that 6 OS-MRSA isolates were able to grow in the presence of up to 8 μg/ml dicloxacillin and 9 isolates were able to grow in 12 to >32 μg/ml dicloxacillin; all isolates grew in up to 2 μg/ml vancomycin. Both drugs exhibited similar bactericidal activities. In experimental infections, the therapeutic efficacy of dicloxacillin was significant (
P
< 0.05 versus untreated controls) in 10 OS-MRSA isolates and vancomycin was effective (
P
< 0.05) against 12 isolates; dicloxacillin had an efficacy that was comparable to that of vancomycin (
P
> 0.05) in 8 isolates. The favorable response to dicloxacillin treatment might suggest that antistaphylococcal penicillins could be used against OS-MRSA infections.
Effects of Rilpivirine on Human Adipocyte Differentiation, Gene Expression, and Release of Adipokines and Cytokines
Authors: Díaz-Delfín Julieta , Domingo Pere , Mateo Maria Gracia , Gutierrez Maria del Mar , Domingo Joan Carles , Giralt Marta , Villarroya Francesc 
Published: March 2012

ABSTRACT

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) recently developed as a drug of choice for initial antiretroviral treatment of HIV-1 infection. Disturbances in lipid metabolism and, ultimately, in adipose tissue distribution and function are common concerns as secondary effects of antiretroviral treatment. Efavirenz, the most commonly used NNRTI, causes mild dyslipidemic effects in patients and strongly impaired adipocyte differentiation
in vitro
. In this study, we provide the first demonstration of the effects of rilpivirine on human adipocyte differentiation, gene expression, and release of regulatory proteins (adipokines and cytokines) and compare them with those caused by efavirenz. Rilpivirine caused a repression of adipocyte differentiation that was associated with impaired expression of the master adipogenesis regulators peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT enhancer binding protein alpha (C/EBPα), and sterol regulatory element binding transcription factor 1 (SREBP-1) and their target genes encoding lipoprotein lipase and the adipokines leptin and adiponectin. Rilpivirine also repressed adiponectin release by adipocytes, but only at high concentrations, and did not alter leptin release. Rilpivirine induced the release of proinflammatory cytokines (interleukin-6 and -8, monocyte chemoattractant protein 1 [MCP-1], plasminogen activator inhibitor type 1 [PAI-1]) only at very high concentrations (10 μM). A comparison of the effects of rilpivirine and efavirenz at the same concentration (4 μM) or even at lower concentrations of efavirenz (2 μM) showed that rilpivirine-induced impairment of adipogenesis and induction of proinflammatory cytokine expression and release were systematically milder than those of efavirenz. It is concluded that rilpivirine causes an antiadipogenic and proinflammatory response pattern, but only at high concentrations, whereas efavirenz causes similar effects at lower concentrations.
Sublimable C5A Delivery Provides Sustained and Prolonged Anti-HIV Microbicidal Activities
Authors: Maskiewicz Richard , Bobardt Michael , Chatterji Udayan , Gunaseelan Simi , Dezzutti Charlene S. , Penin Francois , Gallay Philippe A. 
Published: March 2012

ABSTRACT

We have identified a short amphipathic helical peptide, called C5A, which exhibits potent microbicidal activities
in vitro
and which offers protection from vaginal HIV transmission
in vivo
in a humanized mouse model. However, there are many obstacles to overcome before C5A can be considered a true microbicidal candidate. First, it must be stabilized against enzymatic degradation in a continuously warm and moist environment. Second, it must be delivered in a controlled manner to achieve long-term and coitally independent efficacy. We demonstrate in this
in vitro
study that the combination of two matrices with different subliming properties ((hexamethylcyclotrisiloxane [HMCS] and cyclododecane [CDD]) containing 10% labile C5A yielded the best results in terms of controlled release and preserved anti-HIV activity of the peptide when pre-exposed to cell-free medium or cell culture at body temperature for up to 2 months.
Pharmacokinetics of Ferroquine, a Novel 4-Aminoquinoline, in Asymptomatic Carriers of Plasmodium falciparum Infections
Authors: Supan Christian , Mombo-Ngoma Ghyslain , Dal-Bianco Matthias P. , Ospina Salazar Carmen L. , Issifou Saadou , Mazuir Florent , Filali-Ansary Aziz , Biot Christophe , Ter-Minassian Daniel , Ramharter Michael , Kremsner Peter G. , Lell Bertrand 
Published: March 2012

ABSTRACT

Ferroquine (SSR97193), a ferrocene-quinoline conjugate, is a promising novel antimalarial currently undergoing clinical evaluation. This study characterizes its pharmacokinetic properties. Young male African volunteers with asymptomatic
Plasmodium falciparum
infection were administered a single oral dose (
n
= 40) or a repeated oral dose (
n
= 26) given over 3 days of ferroquine in two dose-escalation, double-blind, randomized, placebo-controlled clinical trials. In addition, a food interaction study was performed in a subsample of participants (
n
= 16). The studies were carried out in Lambaréné, Gabon. After single-dose administration of ferroquine, dose linearity was demonstrated in a dose range of 400 to 1,200 mg for maximum mean blood concentrations ([
C
max
] 82 to 270 ng/ml) and in a dose range of 400 to 1,600 mg for overall exposure to ferroquine (area under the concentration-time curve [AUC], 13,100 to 49,200 ng · h/ml). Overall mean estimate for blood apparent terminal half-life of ferroquine was 16 days and 31 days for its active and major metabolite desmethylferroquine (SSR97213). In the 3-day repeated-dose study,
C
max
and overall cumulated exposure to ferroquine (AUC
cum
) increased in proportion with the dose from day 1 to day 3 between 400 and 800 mg. No major food effect on ferroquine pharmacokinetics was observed after single administration of 100 mg of ferroquine except for a slight delay of time to maximum blood concentration (
t
max
) by approximately 3 h. The pharmacokinetics of ferroquine and its active main metabolite are characterized by sustained levels in blood, and the properties of ferroquine as a partner drug in antimalarial combination therapy should be evaluated.
A Potent Plant-Derived Antifungal Acetylenic Acid Mediates Its Activity by Interfering with Fatty Acid Homeostasis
Authors: Xu Tao , Tripathi Siddharth K. , Feng Qin , Lorenz Michael C. , Wright Marsha A. , Jacob Melissa R. , Mask Melanie M. , Baerson Scott R. , Li Xing-Cong , Clark Alice M. , Agarwal Ameeta K. 
Published: March 2012

ABSTRACT6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogensCandida albicans,Aspergillus fumigatus, andTrichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses were conducted using the model yeastSaccharomyces cerevisiaeto investigate its mechanism of action. 6-NDA elicited a transcriptome response indicative of fatty acid stress, altering the expression of genes that are required for yeast growth in the presence of oleate. Mutants ofS. cerevisiaelacking transcription factors that regulate fatty acid β-oxidation showed increased sensitivity to 6-NDA. Fatty acid profile analysis indicated that 6-NDA inhibited the formation of fatty acids longer than 14 carbons in length. In addition, the growth inhibitory effect of 6-NDA was rescued in the presence of exogenously supplied oleate. To investigate the response of a pathogenic fungal species to 6-NDA, transcriptional profiling and biochemical analyses were also conducted inC. albicans. The transcriptional response and fatty acid profile ofC. albicanswere comparable to those obtained inS. cerevisiae, and the rescue of growth inhibition with exogenous oleate was also observed inC. albicans. In a fluconazole-resistant clinical isolate ofC. albicans, a fungicidal effect was produced when fluconazole was combined with 6-NDA. In hyphal growth assays, 6-NDA inhibited the formation of long hyphal filaments inC. albicans. Collectively, our results indicate that the antifungal activity of 6-NDA is mediated by a disruption in fatty acid homeostasis and that 6-NDA has potential utility in the treatment of superficialCandidainfections.
Rapid, Field-Deployable Method for Genotyping and Discovery of Single-Nucleotide Polymorphisms Associated with Drug Resistance in Plasmodium falciparum
Authors: Daniels Rachel , Ndiaye Daouda , Wall Mikeal , McKinney Jason , Séne Papa Diogoye , Sabeti Pardis C. , Volkman Sarah K. , Mboup Souleymane , Wirth Dyann F. 
Published: March 2012

ABSTRACT

Despite efforts to reduce malaria morbidity and mortality, drug-resistant parasites continue to evade control strategies. Recently, emphasis has shifted away from control and toward regional elimination and global eradication of malaria. Such a campaign requires tools to monitor genetic changes in the parasite that could compromise the effectiveness of antimalarial drugs and undermine eradication programs. These tools must be fast, sensitive, unambiguous, and cost-effective to offer real-time reports of parasite drug susceptibility status across the globe. We have developed and validated a set of genotyping assays using high-resolution melting (HRM) analysis to detect molecular biomarkers associated with drug resistance across six genes in
Plasmodium falciparum
. We improved on existing technical approaches by developing refinements and extensions of HRM, including the use of blocked probes (LunaProbes) and the mutant allele amplification bias (MAAB) technique. To validate the sensitivity and accuracy of our assays, we compared our findings to sequencing results in both culture-adapted lines and clinical isolates from Senegal. We demonstrate that our assays (i) identify both known and novel polymorphisms, (ii) detect multiple genotypes indicative of mixed infections, and (iii) distinguish between variants when multiple copies of a locus are present. These rapid and inexpensive assays can track drug resistance and detect emerging mutations in targeted genetic loci in
P. falciparum
. They provide tools for monitoring molecular changes associated with changes in drug response across populations and for determining whether parasites present after drug treatment are the result of recrudescence or reinfection in clinical settings.
Quinolone-Induced Upregulation of Osteopontin Gene Promoter Activity in Human Lung Epithelial Cell Line A549
Authors: Shiratori Beata , Zhang Jing , Usami Osamu , Chagan-Yasutan Haorile , Suzuki Yasuhiko , Nakajima Chie , Uede Toshimitsu , Hattori Toshio 
Published: March 2012

ABSTRACT
Quinolones, in addition to their antibacterial activities, act as immunomodulators. Osteopontin (OPN), a member of the extracellular matrix proteins, was found to play a role in the immune and inflammatory response. We found that quinolones significantly enhanced OPN secretion, namely, garenoxacin (220%), moxifloxacin (62%), gatifloxacin (82%), sparfloxacin, (79%), and sitafloxacin (60%). Enhancement of OPN secretion was shown to be due to the effect of quinolones on the OPN gene promoter activity. We also examined the role of quinolones on apoptosis and found that sparfloxacin decreased the late apoptosis of A549 cells, but garenoxacin did not show the antiapoptotic effect. The antiapoptotic effects of quinolones do not appear to be associated with OPN elevation.
Characterization of UC781-Tenofovir Combination Gel Products for HIV-1 Infection Prevention in an
Ex Vivo
Ectocervical Model
Authors: Cost Marilyn , Dezzutti Charlene S. , Clark Meredith R. , Friend David R. , Akil Ayman , Rohan Lisa Cencia 
Published: March 2012

ABSTRACT

HIV continues to be a problem worldwide. Topical vaginal microbicides represent one option being evaluated to stop the spread of HIV. With drug candidates that have a specific action against HIV now being studied, it is important that, when appropriate and based on the mechanism of action, the drug permeates the tissue so that it can be delivered to specific targets which reside there. Novel formulations of the nucleotide reverse transcriptase inhibitor tenofovir (TFV) and the nonnucleoside reverse transcriptase inhibitor UC781 have been developed and evaluated here. Gels with three distinct rheological properties were prepared. The three gels released both UC781 and TFV under
in vitro
conditions at concentrations equal to or above the reported 50% effective concentrations (EC
50
s). The drug concentrations in ectocervical tissues were well in excess of the reported EC
50
s. The gels maintain ectocervical viability and prevent infection of ectocervical explants after a HIV-1 challenge. This study successfully demonstrates the feasibility of using this novel combination of antiretroviral agents in an aqueous gel as an HIV infection preventative.
Carbapenem Therapy for Bacteremia Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli or Klebsiella pneumoniae: Implications of Ertapenem Susceptibility
Authors: Lee Nan-Yao , Lee Ching-Chi , Huang Wei-Han , Tsui Ko-Chung , Hsueh Po-Ren , Ko Wen-Chien 
Published: March 2012

ABSTRACT

A retrospective study was conducted at two medical centers in Taiwan to evaluate the clinical characteristics, outcomes, and risk factors for mortality among patients treated with a carbapenem for bacteremia caused by extended-spectrum-beta-lactamase (ESBL)-producing organisms. A total of 251 patients with bacteremia caused by ESBL-producing
Escherichia coli
and
Klebsiella pneumoniae
isolates treated by a carbapenem were identified. Among these ESBL-producing isolates, rates of susceptibility to ertapenem (MICs ≤ 0.25 μg/ml) were 83.8% and 76.4%, respectively; those to meropenem were 100% and 99.3%, respectively; and those to imipenem were 100% and 97.9%, respectively. There were no significant differences in the critical illness rate (
P
= 0.1) or sepsis-related mortality rate (
P
= 0.2) for patients with bacteremia caused by ESBL-producing
K. pneumoniae
(140 isolates, 55.8%) and
E. coli
(111 isolates, 44.2%). Multivariate analysis of variables related to sepsis-related mortality revealed that the presence of severe sepsis (odds ratio [OR], 15.9; 95% confidence interval [CI], 5.84 to 43.34;
P
< 0.001), hospital-onset bacteremia (OR, 4.65; 95% CI, 1.42 to 15.24;
P
= 0.01), and ertapenem-nonsusceptible isolates (OR, 5.12; 95% CI, 2.04 to 12.88;
P
= 0.001) were independent risk factors. The patients receiving inappropriate therapy had a higher sepsis-related mortality than those with appropriate therapy (
P
= 0.002), irrespective of ertapenem, imipenem, or meropenem therapy. Infections due to the ertapenem-susceptible isolates (MICs ≤ 0.25 μg/ml) were associated with a more favorable outcome than those due to ertapenem-nonsusceptible isolates (MICs > 0.25 μg/ml), if treated by a carbapenem. However, the mortality for patients with bacteremic episodes due to isolates with MICs of ≤0.5 μg/ml was similar to the mortality for those whose isolates had MICs of >0.5 μg/ml (
P
= 0.8). Such a finding supports the rationale of the current CLSI 2011 criteria for carbapenems for
Enterobacteriaceae
.
The Combination of Doripenem and Colistin Is Bactericidal and Synergistic against Colistin-Resistant, Carbapenemase-Producing Klebsiella pneumoniae
Authors: Jernigan Meredith G. , Press Ellen G. , Nguyen M. Hong , Clancy Cornelius J. , Shields Ryan K. 
Published: March 2012

ABSTRACT

We tested two-drug combinations of doripenem, colistin, gentamicin, and doxycycline against 12 carbapenemase-producing
Klebsiella pneumoniae
(KPC) isolates by time-kill. The combination of doripenem and colistin reduced the starting inocula by 2 logs for each isolate (range, 2.02 to 6.01 log
10
) and was bactericidal and synergistic against 75 and 50%, respectively. Among colistin- and pan-drug-resistant isolates, synergy was identified in 60 and 67%, respectively. All other combinations were inferior. We are currently evaluating the combination of doripenem and colistin as a frontline therapy for KPC infection.
Pharmacokinetics and Pharmacodynamics of Once-Daily versus Twice-Daily Raltegravir in Treatment-Naïve HIV-Infected Patients
Authors: Rizk Matthew L. , Hang Yaming , Luo Wen-Lin , Su Jing , Zhao Jing , Campbell Havilland , Nguyen Bach-Yen T. , Sklar Peter , Eron Joseph J. , Wenning Larissa 
Published: March 2012

ABSTRACT

QDMRK was a phase III clinical trial of raltegravir given once daily (QD) (800-mg dose) versus twice daily (BID) (400 mg per dose), each in combination with once-daily coformulated tenofovir-emtricitabine, in treatment-naive HIV-infected patients. Pharmacokinetic (PK) and pharmacokinetic/pharmacodynamic (PK/PD) analyses were conducted using a 2-step approach: individual non-model-based PK parameters from observed sparse concentration data were determined, followed by statistical analysis of potential relationships between PK and efficacy response parameters after 48 weeks of treatment. Sparse PK sampling was performed for all patients (QD,
n
= 380; BID,
n
= 384); selected sites performed an intensive PK evaluation at week 4 (QD,
n
= 22; BID,
n
= 20). In the intensive PK subgroup, daily exposures (area under the concentration-time curve from 0 to 24 h [AUC
0–24
]) were similar between the two regimens, but patients on 800 mg QD experienced ∼4-fold-higher maximum drug concentration in plasma (
C
max
) values and ∼6-fold-lower trough drug concentration (
C
trough
) values than those on 400 mg BID. Geometric mean (GM)
C
trough
values were similarly lower in the sparse PK analysis. With BID dosing, there was no indication of any significant PK/PD association over the range of tested PK parameters. With QD dosing,
C
trough
values correlated with the likelihood of virologic response. Failure to achieve an HIV RNA level of <50 copies/ml appeared predominantly at high baseline HIV RNA levels in both treatment arms and was associated with lower values of GM
C
trough
in the 800-mg-QD arm, though other possible drivers of efficacy, such as time above a threshold concentration, could not be evaluated due to the sparse sampling scheme. Together, these findings emphasize the importance of the shape of the plasma concentration-versus-time curve for long-term efficacy.
Regulation of Cytokine and Chemokine Expression by the Ribotoxic Stress Response Elicited by Shiga Toxin Type 1 in Human Macrophage-Like THP-1 Cells
Authors: Leyva-Illades Dinorah , Cherla Rama P. , Lee Moo-Seung , Tesh Vernon L. 
Published: March 2012

ABSTRACTShiga toxins (Stxs) are cytotoxins produced by the enteric pathogensShigella dysenteriaeserotype 1 and Shiga toxin-producingEscherichia coli(STEC). Stxs bind to a membrane glycolipid receptor, enter cells, and undergo retrograde transport to ultimately reach the cytosol, where the toxins exert their protein synthesis-inhibitory activity by depurination of a single adenine residue from the 28S rRNA component of eukaryotic ribosomes. The depurination reaction activates the ribotoxic stress response, leading to signaling via the mitogen-activated protein kinase (MAPK) pathways (Jun N-terminal protein kinase [JNK], p38, and extracellular signal-regulated kinase [ERK]) in human epithelial, endothelial, and myeloid cells. We previously showed that treatment of human macrophage-like THP-1 cells with Stxs resulted in increased cytokine and chemokine expression. In the present study, we show that individual inactivation of ERK, JNK, and p38 MAPKs using pharmacological inhibitors in the presence of Stx1 resulted in differential regulation of the cytokines tumor necrosis factor alpha and interleukin-1β (IL-1β) and chemokines IL-8, growth-regulated protein-β, macrophage inflammatory protein-1α (MIP-1α), and MIP-1β. THP-1 cells exposed to Stx1 upregulate the expression of select dual-specificity phosphatases (DUSPs), enzymes that dephosphorylate and inactivate MAPKs in mammalian cells. In this study, we confirmed DUSP1 protein production by THP-1 cells treated with Stx1. DUSP1 inhibition by triptolide showed that ERK and p38 phosphorylation is regulated by DUSP1, while JNK phosphorylation is not. Inhibition of p38 MAPK signaling blocked the ability of Stx1 to induce DUSP1 mRNA expression, suggesting that an autoregulatory signaling loop may be activated by Stxs. Thus, Stxs appear to be capable of eliciting signals which both activate and deactivate signaling for increased cytokine/chemokine production in human macrophage-like cells.
ON-LINE CONSTRUCTION OF A SMALL AUTOMATON FOR A FINITE SET OF WORDS
Authors: CROCHEMORE MAXIME , GIAMBRUNO LAURA , LANGIU ALESSIO 
Published: March 2012

In this paper we describe a "light" algorithm for the on-line construction of a small automaton recognising a finite set of words. The algorithm runs in linear time. We carried out good experimental results on real dictionaries, on biological sequences and on the sets of suffixes (resp. factors) of a set of words that shows how our automaton is near to the minimal one. For the suffixes of a text, we propose a modified construction that leads to an even smaller automaton. We moreover construct linear algorithms for the insertion and deletion of a word in a finite set, directly from the constructed automaton.