bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of a Single Dose of Ritonavir on the Pharmacokinetic Behavior of Elvucitabine, a Nucleoside Reverse Transcriptase Inhibitor, Administered in Healthy Volunteers
Authors: Colucci Philippe , Pottage John C. , Robison Heather , Turgeon Jacques , Ducharme Murray P. 
Published: November 2008

ABSTRACTThe purpose of this study was to determine the effect of a single dose of 300 mg of ritonavir on the plasma pharmacokinetics (PK) of a single dose of 20 mg of elvucitabine when the two drugs were coadministered in healthy subjects. In a three-way crossover design, 30 subjects received 20 mg of elvucitabine, 300 mg of ritonavir, or 20 mg of elvucitabine coadministered with 300 mg of ritonavir. Elvucitabine concentrations were analyzed using a validated liquid chromatography-tandem mass spectrometry assay. The PK of elvucitabine was determined using both noncompartmental and compartmental analyses. Models were developed and tested using ADAPT-II, while a population analysis was performed using IT2S. Comparisons of PK parameters between groups were done with SAS. The pharmacokinetic behavior of elvucitabine was best described by a two-compartment linear model using two absorption rates and a first-order elimination rate. Ritonavir significantly impacted the PK of elvucitabine by reducing elvucitabine's bioavailability, with the most plausible explanation being an inhibition on influx transporters by ritonavir. The decrease in elvucitabine bioavailability when elvucitabine was coadministered with ritonavir may be due to ritonavir's inhibiting influx gut transporters. Continued development of elvucitabine is warranted to better characterize its PK and to determine its in vivo efficacy against human immunodeficiency virus.
Safety, Pharmacokinetics, and Antiretroviral Activity of Multiple Doses of Ibalizumab (formerly TNX-355), an Anti-CD4 Monoclonal Antibody, in Human Immunodeficiency Virus Type 1-Infected Adults
Authors: Jacobson Jeffrey M. , Kuritzkes Daniel R. , Godofsky Eliot , DeJesus Edwin , Larson Jeffrey A. , Weinheimer Steven P. , Lewis Stanley T. 
Published: November 2008

ABSTRACTIbalizumab (formerly TNX-355) is a humanized monoclonal antibody that binds CD4, the primary receptor for human immunodeficiency virus type 1 (HIV-1), and inhibits the viral entry process. A phase lb multidose study of the safety, pharmacokinetics, and antiviral activity of ibalizumab was conducted with 22 HIV-1-infected patients. Nineteen patients were randomized to receive either 10 mg/kg of body weight weekly (arm A) or a 10-mg/kg loading dose followed by 6 mg/kg every 2 weeks (arm B) intravenously for 9 weeks. Three patients were assigned to receive 25 mg/kg every 2 weeks for five doses (arm C). During the study, the patients remained off other antiretrovirals or continued a stable failing regimen. Treatment with ibalizumab resulted in substantial reductions in HIV-1 RNA levels (0.5 to 1.7 log10) in 20 of 22 subjects. In most patients, HIV-1 RNA fell to nadir levels after 1 to 2 weeks of treatment and then returned to baseline despite continued treatment. Baseline viral isolates were susceptible to ibalizumab in vitro, regardless of coreceptor tropism. Emerging resistance to ibalizumab was manifested by reduced maximal percent inhibition in a single-cycle HIV infectivity assay. Resistant isolates remained CD4 dependent and were susceptible to enfuvirtide in vitro. Complete coating of CD4+T-cell receptors was correlated with serum ibalizumab concentrations. There was no evidence of CD4+T-cell depletion in ibalizumab-treated patients. Ibalizumab was not immunogenic, and no serious drug-related adverse effects occurred. In conclusion, ibalizumab administered either weekly or biweekly was safe and well tolerated and demonstrated antiviral activity. Further studies with ibalizumab in combination with standard antiretroviral treatments are warranted.
Daptomycin Pharmacokinetics in Adult Oncology Patients with Neutropenic Fever
Authors: Bubalo Joseph S. , Munar Myrna Y. , Cherala Ganesh , Hayes-Lattin Brandon , Maziarz Richard 
Published: November 2008

ABSTRACT

Daptomycin is the first antibacterial agent of the cyclic lipopeptides with in vitro bactericidal activity against gram-positive organisms, including vancomycin-resistant enterococci, methicillin-resistant staphylococci, and glycopeptide-resistant
Staphylococcus aureus
. The pharmacokinetics of daptomycin were determined in 29 adult oncology patients with neutropenic fever. Serial blood samples were drawn at 0, 0.5, 1, 2, 4, 8, 12, and 24 h after the initial intravenous infusion of 6 mg/kg of body weight daptomycin. Daptomycin total and free plasma concentrations were determined by high-pressure liquid chromatography. Concentration-time data were analyzed by noncompartmental methods. The results (presented as means ± standard deviations and ranges, unless indicated otherwise) were as follows: the maximum concentration of drug in plasma (
C
max
) was 49.04 ± 12.42 μg/ml (range, 21.54 to 75.20 μg/ml), the 24-h plasma concentration was 6.48 ± 5.31 μg/ml (range, 1.48 to 29.26 μg/ml), the area under the concentration-time curve (AUC) from time zero to infinity was 521.37 ± 523.53 μg·h/ml (range, 164.64 to 3155.11 μg·h/ml), the volume of distribution at steady state was 0.18 ± 0.05 liters/kg (range, 0.13 to 0.36 liters/kg), the clearance was 15.04 ± 6.09 ml/h/kg (range, 1.90 to 34.76 ml/h/kg), the half-life was 11.34 ± 14.15 h (range, 5.17 to 83.92 h), the mean residence time was 15.67 ± 20.66 h (range, 7.00 to 121.73 h), and the median time to
C
max
was 0.6 h (range, 0.5 to 2.5 h). The fraction unbound in the plasma was 0.06 ± 0.02. All patients achieved
C
max
/MIC and AUC from time zero to 24 h (AUC
0-24
)/MIC ratios for a bacteriostatic effect against
Streptococcus pneumoniae
. Twenty-seven patients (93%) achieved a
C
max
/MIC ratio for a bacteriostatic effect against
S. aureus
, and 28 patients (97%) achieved an AUC
0-24
/MIC ratio for a bacteriostatic effect against
S. aureus
. Free plasma daptomycin concentrations were above the MIC for 50 to 100% of the dosing interval in 100% of patients for
S. pneumoniae
and 90% of patients for
S. aureus
. The median time to defervescence was 3 days from the start of daptomycin therapy. In summary, a 6-mg/kg intravenous infusion of daptomycin every 24 h was effective and well tolerated in neutropenic cancer patients.
Ambuic Acid Inhibits the Biosynthesis of Cyclic Peptide Quormones in Gram-Positive Bacteria
Authors: Nakayama Jiro , Uemura Yumi , Nishiguchi Kenzo , Yoshimura Norito , Igarashi Yasuhiro , Sonomoto Kenji 
Published: November 2008

ABSTRACT

Quorum sensing is a cell-density-dependent regulatory system in gram-positive bacteria and is often regulated by cyclic peptides called “quormones,” which function as extracellular communication signals. With an aim to discover an antipathogenic agent targeting quorum sensing in gram-positive bacteria, we screened 153 samples of fungal butanol extracts with the guidance of the inhibition of quorum-sensing-mediated gelatinase production in
Enterococcus faecalis
. Following the screenings, we found that ambuic acid, a known secondary fungal metabolite, inhibited the quorum-sensing-mediated gelatinase production without influencing the growth of
E. faecalis.
We further demonstrated that ambuic acid targeted the biosynthesis of a cyclic peptide quormone called gelatinase biosynthesis-activating pheromone. Furthermore, ambuic acid also inhibited the biosynthesis of the cyclic peptide quormones of
Staphylococcus aureus
and
Listeria innocua.
These results suggest the potential use of ambuic acid as a lead compound of antipathogenic drugs that target the quorum-sensing-mediated virulence expression of gram-positive bacteria.
Impact of Inoculum Size and Heterogeneous Vancomycin-Intermediate
Staphylococcus aureus
(hVISA) on Vancomycin Activity and Emergence of VISA in an In Vitro Pharmacodynamic Model
Authors: Rose Warren E. , Leonard Steven N. , Rossi Kerri L. , Kaatz Glenn W. , Rybak Michael J. 
Published: November 2008

ABSTRACT

The activity of vancomycin against heterogeneous vancomycin-intermediate
Staphylococcus aureus
(hVISA) and non-hVISA isolates, using an in vitro pharmacodynamic model, was reduced in the presence of a high inoculum amount (10
8
CFU/ml). A high bacterial load of >10
5
CFU/ml persisted for all strains with doses up to 5 g every 12 h against high inoculum amounts. No change in the vancomycin MIC was detected in any isolate at a moderate inoculum amount (10
6
CFU/ml), and bactericidal activity occurred only against the non-hVISA isolate (time to 99% kill, 7.5 h;
P
= 0.001).
Truncated
tni
Module Adjacent to the Complex Integron of
Salmonella
Genomic Island 1 in
Salmonella enterica
Serovar Virchow
Authors: Doublet Benoît , Chu Chishih , Chiu Cheng-Hsun , Fan Yi-Chin , Cloeckaert Axel 
Published: November 2008

ABSTRACT

Salmonella
genomic island 1 was identified for the first time in
Salmonella enterica
serovar Virchow isolated from humans in Taiwan. The complex class 1 integron conferring multidrug resistance was shown to be inserted within open reading frame (ORF) S023 and contains for the first time a partial transpositional module. The 5-bp target duplication flanking the complex integron suggests that its insertion in ORF S023 was by transposition.
Activity of Levofloxacin Alone and in Combination with a DnaK Inhibitor against Gram-Negative Rods, Including Levofloxacin-Resistant Strains
Authors: Credito Kim , Lin Gengrong , Koeth Laura , Sturgess Michael A. , Appelbaum Peter C. 
Published: November 2008

ABSTRACTSynergy time-kill testing of levofloxacin alone and in combination with CHP-105, a representative DnaK inhibitor, against 50 gram-negative rods demonstrated that 34 of the 50 strains tested showed significant synergy between levofloxacin and CHP-105 after 12 h and 24 h. Fourteen of these 34 organisms were quinolone resistant (levofloxacin MICs of ≥4 μg/ml).
In Vitro and In Vivo Properties of Ellagic Acid in Malaria Treatment
Authors: Soh Patrice Njomnang , Witkowski Benoît , Olagnier David , Nicolau Marie-Laure , Garcia-Alvarez Maria-Concepcion , Berry Antoine , Benoit-Vical Françoise 
Published: November 2008

ABSTRACT

Malaria is one of the most significant causes of infectious disease in the world. The search for new antimalarial chemotherapies has become increasingly urgent due to the parasites’ resistance to current drugs. Ellagic acid is a polyphenol found in various plant products. In this study, antimalarial properties of ellagic acid were explored. The results obtained have shown high activity in vitro against all
Plasmodium falciparum
strains whatever their levels of chloroquine and mefloquine resistance (50% inhibitory concentrations ranging from 105 to 330 nM). Ellagic acid was also active in vivo against
Plamodium vinckei petteri
in suppressive, curative, and prophylactic murine tests, without any toxicity (50% effective dose by the intraperitoneal route inferior to 1 mg/kg/day). The study of the point of action of its antimalarial activity in the erythrocytic cycle of
Plasmodium falciparum
demonstrated that it occurred at the mature trophozoite and young schizont stages. Moreover, ellagic acid has been shown to potentiate the activity of current antimalarial drugs such as chloroquine, mefloquine, artesunate, and atovaquone. This study also proved the antioxidant activity of ellagic acid and, in contrast, the inhibitory effect of the antioxidant compound
N
-acetyl-
l
-cysteine on its antimalarial efficacy. The possible mechanisms of action of ellagic acid on
P. falciparum
are discussed in light of the results. Ellagic acid has in vivo activity against plasmodia, but modification of the compound could lead to improved pharmacological properties, principally for the oral route.
In Vitro Susceptibility of Field Isolates of
Leishmania donovani
to Miltefosine and Amphotericin B: Correlation with Sodium Antimony Gluconate Susceptibility and Implications for Treatment in Areas of Endemicity
Authors: Kumar Dhiraj , Kulshrestha Arpita , Singh Ruchi , Salotra Poonam 
Published: November 2008

ABSTRACT

Indian
Leishmania donovani
isolates (
n
= 19) from regional zones representing various levels of antimony resistance displayed significantly (
P
< 0.01) correlated results with respect to in vitro susceptibility to the antileishmanial drugs sodium antimony gluconate, amphotericin B, and Miltefosine, raising the possibility of cross-resistance mechanisms operating in the field isolates. The results of gene expression analysis of LdMT and LdRos3 were suggestive of alternate mechanisms of Miltefosine susceptibility in the isolates.
Activity of the Oral Neuraminidase Inhibitor A-322278 against the Oseltamivir-Resistant H274Y (A/H1N1) Influenza Virus Mutant in Mice
Authors: Baz Mariana , Abed Yacine , Nehmé Benjamin , Boivin Guy 
Published: November 2008

ABSTRACTThe new oral neuraminidase (NA) inhibitor A-322278 was evaluated in mice infected with influenza A/H1N1 wild-type virus or the oseltamivir-resistant (H274Y mutant) virus. A-322278 decreased mortality rates and lung virus titers significantly more than oseltamivir in mice infected with the NA H274Y mutant when therapy was started 4 h before or even 48 h after infection.
Human Decay-Accelerating Factor and CEACAM Receptor-Mediated Internalization and Intracellular Lifestyle of Afa/Dr Diffusely Adhering
Escherichia coli
in Epithelial Cells
Authors: Guignot Julie , Hudault Sylvie , Kansau Imad , Chau Ingrid , Servin Alain L. 
Published: November 2008

ABSTRACT

We used transfected epithelial CHO-B2 cells as a model to identify the mechanism mediating internalization of Afa/Dr diffusely adhering
Escherichia coli
. We provide evidence that neither the α5 or β1 integrin subunits nor α5β1 integrin functioned as a receptor mediating the adhesion and/or internalization of Dr or Afa-III fimbria-positive bacteria. We also demonstrated that (i) whether or not the AfaD or DraD invasin subunits were present, there was no difference in the cell association and entry of bacteria and that (ii) DraE or AfaE-III adhesin subunits are necessary and sufficient to promote the receptor-mediated bacterial internalization into epithelial cells expressing human decay-accelerating factor (DAF), CEACAM1, CEA, or CEACAM6. Internalization of Dr fimbria-positive
E. coli
within CHO-DAF, CHO-CEACAM1, CHO-CEA, or CHO-CEACAM6 cells occurs through a microfilament-independent, microtubule-dependent, and lipid raft-dependent mechanism. Wild-type Dr fimbria-positive bacteria survived better within cells expressing DAF than bacteria internalized within CHO-CEACAM1, CHO-CEA, or CHO-CEACAM6 cells. In DAF-positive cells, internalized Dr fimbria-positive bacteria were located in vacuoles that contained more than one bacterium, displaying some of the features of late endosomes, including the presence of Lamp-1 and Lamp-2, and some of the features of CD63 proteins, but not of cathepsin D, and were acidic. No interaction between Dr fimbria-positive-bacterium-containing vacuoles and the autophagic pathway was observed.
Immunodominance in Mouse and Human CD4+T-Cell Responses Specific for theBordetella pertussisVirulence Factor P.69 Pertactin
Authors: Stenger Rachel M. , Poelen Martien C. M. , Moret Ed E. , Kuipers Betsy , Bruijns Sven C. M. , Hoogerhout Peter , Hijnen Marcel , King Audrey J. , Mooi Frits R. , Boog Claire J. P. , van Els Cécile A. C. M. 
Published: November 2008

ABSTRACTP.69 pertactin (P.69 Prn), an adhesion molecule from the causative agent of pertussis,Bordetella pertussis, is present in cellular and most acellular vaccines that are currently used worldwide. Although both humoral immunity and cellular immunity directed against P.69 Prn have been implicated in protective immune mechanisms, the identities of CD4+T-cell epitopes on the P.69 Prn protein remain unknown. Here, a single I-Ad-restrictedB. pertussisconserved CD4+T-cell epitope at the N terminus of P.69 Prn was identified by using a BALB/c T-cell hybridoma. The epitope appeared immunodominant among four other minor strain-conserved P.69 Prn epitopes recognized after vaccination andB. pertussisinfection, and it was capable of evoking a Th1/Th17-type cytokine response.B. pertussisP.69 Prn immune splenocytes did not cross-react with natural variants of the epitope as present inBordetella parapertussisandBordetella bronchiseptica. Finally, it was found that the immunodominant P.69 Prn epitope is broadly recognized in the human population by CD4+T cells in an HLA-DQ-restricted manner. DuringB. pertussisinfection, the epitope was associated with a Th1-type CD4+T-cell response. Hence, this novel P.69 Prn epitope is involved in CD4+T-cell immunity afterB. pertussisvaccination and infection in mice and, more importantly, in humans. Thus, it may provide a useful tool for the evaluation of the type, magnitude, and maintenance ofB. pertussis-specific CD4+T-cell mechanisms in preclinical and clinical vaccine studies.
Localization of the Domains of the
Haemophilus ducreyi
Trimeric Autotransporter DsrA Involved in Serum Resistance and Binding to the Extracellular Matrix Proteins Fibronectin and Vitronectin
Authors: Leduc Isabelle , Olsen Bonnie , Elkins Christopher 
Published: November 2008

ABSTRACT

Resisting the bactericidal activity of naturally occurring antibodies and complement of normal human serum is an important element in the evasion of innate immunity by bacteria. In the gram-negative mucosal pathogen
Haemophilus ducreyi
, serum resistance is mediated primarily by the trimeric autotransporter DsrA. DsrA also functions as an adhesin for the extracellular matrix proteins fibronectin and vitronectin and mediates attachment of
H. ducreyi
to keratinocytes. We sought to determine the domain(s) of the 236-residue DsrA protein required for serum resistance and extracellular matrix protein binding. A 140-amino-acid truncated protein containing only the C-terminal portion of the passenger domain and the entire translocator domain of DsrA exhibited binding to fibronectin and vitronectin and conferred serum resistance to an
H. ducreyi
serum-sensitive strain. A shorter DsrA construct consisting of only 128 amino acids was unable to bind to extracellular matrix proteins but was serum resistant. We concluded that neither fibronectin binding nor vitronectin binding is required for high-level serum resistance in
H. ducreyi
.
Humoral Immunity against Capsule Polysaccharide Protects the Host from
magA
+
Klebsiella pneumoniae
-Induced Lethal Disease by Evading Toll-Like Receptor 4 Signaling
Authors: Wu Ming-Fang , Yang Chih-Ya , Lin Tzu-Lung , Wang Jin-Town , Yang Feng-Ling , Wu Shih-Hsiung , Hu Bor-Shen , Chou Teh-Ying , Tsai Ming-Daw , Lin Chi-Hung , Hsieh Shie-Liang 
Published: November 2008

ABSTRACT

Klebsiella pneumoniae magA
(for mucoviscosity-associated gene A) is linked to the pathogenesis of primary pyogenic liver abscess, but the underlying mechanism by which
magA
increases pathogenicity is not well elucidated. In this study, we investigated the role of the capsular polysaccharides (CPS) in the pathogenesis of
magA
+
K. pneumoniae
by comparing host immunity to
magA
+
K. pneumoniae
and a Δ
magA
mutant. We found that Toll-like receptor 4 recognition by
magA
+
K. pneumoniae
was hampered by the mucoviscosity of the
magA
+
K. pneumoniae
CPS. Interestingly, monoclonal antibodies (MAbs) against
magA
+
K. pneumoniae
CPS recognized all of the K1 strains tested but not the Δ
magA
and non-K1 strains. Moreover, the anti-CPS MAbs protected mice from
magA
+
K. pneumoniae
-induced liver abscess formation and lethality. This indicates that the K1 epitope is a promising target for vaccine development, and anti-CPS MAbs has great potential to protect host from K1 strain-induced mortality and morbidity in diabetic and other immunocompromised patients in the future.
Immune Response and Alveolar Bone Resorption in a Mouse Model ofTreponema denticolaInfection
Authors: Lee Song F. , Andrian Elisoa , Rowland Elden , Marquez Ignacio Christian 
Published: November 2008

ABSTRACTTreponema denticolais considered to be an agent strongly associated with periodontal disease. The lack of an animal infection model has hampered the understanding ofT. denticolapathogenesis and the host's immune response to infection. In this study, we have established an oral infection model in mice, demonstrating that infection by oral inoculation is feasible. The presence ofT. denticolain the oral cavities of the animals was confirmed by PCR. Mice givenT. denticoladeveloped a specific immune response to the bacterium. The antibodies generated from the infection were mainly of the immunoglobulin G1 subclass, indicating a Th2-tilted response. The antibodies recognized 11T. denticolaproteins, of which a 62-kDa and a 53-kDa protein were deemed immunodominant. The two proteins were identified, respectively, as dentilisin and the major outer sheath protein by mass spectrometry. Splenocytes cultured from the infected mice no longer produced interleukin-10 and produced markedly reduced levels of gamma interferon relative to those produced by naïve splenocytes upon stimulation withT. denticola. Mandibles of infected mice showed significantly greater bone resorption (P< 0.01) than those of mock-infected controls.
Effect ofPlasmodium yoeliiExposure on Vaccination with the 19-Kilodalton Carboxyl Terminus of Merozoite Surface Protein 1 and Vice Versa and Implications for the Application of a Human Malaria Vaccine
Authors: Wipasa Jiraprapa , Xu Huji , Liu Xueqin , Hirunpetcharat Chakrit , Stowers Anthony , Good Michael F. 
Published: November 2008

ABSTRACTIt is well known that exposure to one antigen can modulate the immune responses that develop following exposure to closely related antigens. It is also known that the composition of the repertoire can be skewed to favor epitopes shared between a current infection and a preceding one, a phenomenon referred to as “original antigenic sin.” It was of interest, therefore, to investigate the antibody response that develops following exposure to the malaria vaccine candidate homologuePlasmodium yoeliiMSP119in mice that had previously experienced malaria infection and vice versa. In this study, preexposure of mice toPlasmodium yoeliielicited native anti-MSP119antibody responses, which could be boosted by vaccination with recombinant MSP119. Likewise, infection of MSP119-primed mice withP. yoeliiled to an increase of anti-MSP119antibodies. However, this increase was at the expense of antibodies to parasite determinants other than MSP119. This change in the balance of antibody specificities significantly affected the ability of mice to withstand a subsequent infection. These data have particular relevance to the possible outcome of malaria vaccination for those situations where the vaccine response is suboptimal and suggest that suboptimal vaccination may in fact render the ultimate acquisition of natural immunity more difficult.