bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tiludronate infusion in the treatment of bone spavin: A double blind placebo‐controlled trial
Authors: GOUGH M. R. , THIBAUD D. , SMITH R. K. W. 
Published: June 2010

SummaryReasons for performing study: Tiludronate regulates bone remodelling through a decrease of the resorptive process and should therefore ameliorate the remodelling processes active in osteoarthritis of the distal tarsal joints (‘bone spavin’) and alleviate pain associated with abnormal bone lysis.Objective: To confirm the efficacy of tiludronate, administered as a single infusion at a dose of 1 mg/kg bwt, in the treatment of bone spavin in the horse.Methods: A double blind placebo controlled trial on 108 clinical cases of bone spavin was undertaken. The lameness score of the lamest limb was assessed following distal tarsal analgesia of the contralateral limb and followed‐up using the same procedure throughout the study. Bone spavin in the lamest limb was confirmed by distal tarsal analgesia and radiography. Horses were treated at Day 0 and reassessed 60 days later after controlled exercise. A second nonblinded treatment was given to unresponsive horses and all horses were re‐examined at Day 120. Exercise levels were recorded at each examination.Results: Eighty‐seven horses completed the trial as per the protocol. The tiludronate horses were significantly less lame than the placebo horses (P = 0.0318). Horses treated at Day 60 with tiludronate showed further improvement in lameness at Day 120 (P = 0.0096 and P = 0.0034 for horses treated with tiludronate and placebo at Day 0, respectively). The only significant difference in radiographic findings between tiludronate and placebo was for presence of periarticular osteophytes (P = 0.006).Conclusions: Tiludronate treatment is proven to be effective in bone spavin in horses in association with a controlled exercise programme.Clinical relevance: Tiludronate in combination with controlled exercise offers an alternate medical treatment for bone spavin.
Experimental Murine Scedosporiosis: Histopathology and Azole Treatment
Authors: Rodríguez M. Mar , Pastor F. Javier , Salas Valentina , Calvo Enrique , Mayayo Emilio , Guarro Josep 
Published: June 2010

ABSTRACT

The histopathology of clinical isolates of
Scedosporium apiospermum
,
Scedosporium boydii
, and
Scedosporium aurantiacum
in immunosuppressed mice was evaluated. The organs most affected were the brain, kidneys, and spleen.
S. aurantiacum
produced more tissue damage than the other two species. Amphotericin B (AMB) was ineffective in the treatment of murine infections caused by such isolates, and posaconazole and voriconazole showed efficacy that correlated with the
in vitro
susceptibility data.
Extended-Spectrum Cephalosporinase in
Acinetobacter baumannii
Authors: Rodríguez-Martínez José-Manuel , Nordmann Patrice , Ronco Esthel , Poirel Laurent 
Published: June 2010

ABSTRACT

An AmpC-type β-lactamase conferring high-level resistance to expanded-spectrum cephalosporins and monobactams was characterized from an
Acinetobacter baumannii
clinical isolate. This class C β-lactamase (named ADC-33) possessed a Pro210Arg substitution together with a duplication of an Ala residue at position 215 (inside the Ω-loop) compared to a reference AmpC cephalosporinase from
A. baumannii
. ADC-33 hydrolyzed ceftazidime, cefepime, and aztreonam at high levels, which allows the classification of this enzyme as an extended-spectrum AmpC (ESAC). Site-directed mutagenesis confirmed the role of both substitutions in its ESAC property.
Baseline Genotypic and Phenotypic Susceptibilities of HIV-1 Group O to Enfuvirtide
Authors: Depatureaux Agnès , Charpentier Charlotte , Collin Gilles , Leoz Marie , Descamps Diane , Vessière Aurélia , Damond Florence , Rousset Dominique , Brun-Vézinet Françoise , Plantier Jean-Christophe 
Published: June 2010

ABSTRACTWe assessed the natural genotypic and phenotypic susceptibilities to enfuvirtide of 171 HIV group O (HIV-O) samples and 29 strains, respectively. The N42D resistance-associated mutation in the gp41 region was detected in 98% of cases. The phenotypic assay showed a wide range of baseline susceptibilities, with 50% inhibitory concentrations (IC50s) from 4 to 5,000 nM, a range similar to that reported for HIV-1 group M. Thus, despite the natural genotypic resistance conferred by the N42D signature mutation, HIV-O variants appear to be phenotypically susceptible. Enfuvirtide could therefore potentially be used in antiretroviral treatments for HIV-O-infected patients.
Therapeutic Drug Monitoring of Posaconazole in Hematology Patients: Experience with a New High-Performance Liquid Chromatography-Based Method
Authors: Neubauer Werner Christian , Engelhardt Monika , König Armin , Hieke Stefanie , Jung Manfred , Bertz Hartmut , Kümmerer Klaus 
Published: June 2010

ABSTRACT

Parallel administration of the proton pump inhibitor (PPI) esomeprazole has been shown to decrease oral bioavailability of posaconazole in healthy volunteers. We prospectively analyzed serum samples (
n
= 59) obtained from hematology patients (
n
= 27) under posaconazole prophylaxis. Patients treated concomitantly with pantoprazole had significantly lower posaconazole levels than patients without PPI treatment (median levels of 630 μg/liter versus 1,125 μg/liter, respectively). These results suggest that drug monitoring is relevant when posaconazole and pantoprazole are administered concomitantly.
Absence of Association between Piperaquine
In Vitro
Responses and Polymorphisms in the
pfcrt
,
pfmdr1
,
pfmrp
, and
pfnhe
Genes in
Plasmodium falciparum
Authors: Briolant Sébastien , Henry Maud , Oeuvray Claude , Amalvict Rémy , Baret Eric , Didillon Eric , Rogier Christophe , Pradines Bruno 
Published: June 2010

ABSTRACT

We have analyzed the profiles of 23 of
Plasmodium falciparum
strains for their
in vitro
chemosusceptibilities to piperaquine (PPQ), dihydroartemisinin (DHA), chloroquine, monodesethylamodiaquine, quinine, mefloquine, lumefantrine, atovaquone, pyrimethamine, and doxycycline (DOX) in association with polymorphisms in genes involved in quinoline resistance (
Plasmodium falciparum crt
[
pfcrt
],
pfmdr1
,
pfmrp
, and
pfnhe
). The 50% inhibitory concentrations (IC
50
s) for PPQ ranged from 29 to 98 nM (geometric mean = 57.8 nM, 95% confidence interval [CI] = 51 to 65) and from 0.4 to 5.8 nM for DHA (geometric mean = 1.8 nM, 95% CI = 1.4 to 2.3). We found a significant positive correlation between the responses to PPQ and DHA (
r
2
= 0.17;
P
= 0.0495) and between the responses to PPQ and DOX (
r
2
= 0.41;
P
= 0.001). We did not find a significant association between the PPQ IC
50
(0.0525 <
P
< 0.9247) or the DHA IC
50
(0.0138 <
P
< 0.9018) and polymorphisms in the
pfcrt
,
pfmdr1
,
pfmrp
, and
pfnhe-1
genes. There was an absence of cross-resistance with quinolines, and the IC
50
s for PPQ and DHA were found to be unrelated to mutations in the
pfcrt
,
pfmdr1
,
pfmrp
, and
pfnhe-1
transport protein genes, which are involved in quinoline antimalarial drug resistance. These results confirm the interest in and the efficacy of the combination of PPQ and DHA for areas in which parasites are resistant to chloroquine or other quinolines.
Foreign Travel Is a Major Risk Factor for Colonization with
Escherichia coli
Producing CTX-M-Type Extended-Spectrum β-Lactamases: a Prospective Study with Swedish Volunteers
Authors: Tängdén Thomas , Cars Otto , Melhus Åsa , Löwdin Elisabeth 
Published: June 2010

ABSTRACT

Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing
Enterobacteriaceae
. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associated risk factors were collected before and after traveling. A total of 105 volunteers were enrolled. Four of them did not complete the study, and one participant carried ESBL-producing
Escherichia coli
before travel. Twenty-four of 100 participants with negative pretravel samples were colonized with ESBL-producing
Escherichia coli
after the trip. All strains produced CTX-M enzymes, mostly CTX-M-15, and some coproduced TEM or SHV enzymes. Coresistance to several antibiotic subclasses was common. Travel to India was associated with the highest risk for the acquisition of ESBLs (88%;
n
= 7). Gastroenteritis during the trip was an additional risk factor (
P
= 0.003). Five of 21 volunteers who completed the follow-up after 6 months had persistent colonization with ESBLs. This is the first prospective study demonstrating that international travel is a major risk factor for colonization with ESBL-producing
Enterobacteriaceae
. Considering the high acquisition rate of 24%, it is obvious that global efforts are needed to meet the emergence and spread of CTX-M enzymes and other antimicrobial resistances.
Using Population Pharmacokinetics To Determine Gentamicin Dosing during Extended Daily Diafiltration in Critically Ill Patients with Acute Kidney Injury
Authors: Roberts Jason A. , Field Jonathan , Visser Adam , Whitbread Rosemary , Tallot Mandy , Lipman Jeffrey , Kirkpatrick Carl M. J. 
Published: June 2010

ABSTRACT

The objective of the present prospective pharmacokinetic study was to describe the variability of plasma gentamicin concentrations in critically ill patients with acute kidney injury (AKI) necessitating extended daily diafiltration (EDD-f) using a population pharmacokinetic model and to subsequently perform Monte Carlo dosing simulations to determine which dose regimen achieves the pharmacodynamic targets the most consistently. We collected data from 28 gentamicin doses in 14 critically ill adult patients with AKI requiring EDD-f and therapeutic gentamicin. Serial plasma samples were collected. A population pharmacokinetic model was used to describe the pharmacokinetics of gentamicin and perform Monte Carlo simulations with doses of between 3 mg/kg of body weight and 7 mg/kg and at various time points before commencement of EDD-f to evaluate the optimal dosing regimen for achieving pharmacodynamic targets. A two-compartment pharmacokinetic model adequately described the gentamicin clearance while patients were on and off EDD-f. The plasma half-life of gentamicin during EDD-f was 13.8 h, whereas it was 153.4 h without EDD-f. Monte Carlo simulations suggest that dosing with 6 mg/kg every 48 h either 30 min or 1 h before the commencement of EDD-f results in 100% attainment of the target maximum concentration drug in plasma (<10 mg/liter) and sufficient attainment of the target area under the concentration-time curve from 0 to 24 h (AUC
0-24
; 70 to 120 mg·h/liter). None of the simulated dosing regimens satisfactorily achieved the targets of the minimum concentrations of drug in plasma (<1.0 mg/liter) at 24 h. In conclusion, dosing of gentamicin 30 min to 1 h before the commencement of an EDD-f treatment enables attainment of target peak concentrations for maximal therapeutic effect while enhancing drug clearance to minimize toxicity. Redosing in many patients should occur after 48 h, and we recommend the use of therapeutic drug monitoring to guide dosing to optimize achievement of the AUC
0-24
targets.
Affinity of the New Cephalosporin CXA-101 to Penicillin-Binding Proteins ofPseudomonas aeruginosa
Authors: Moyá Bartolomé , Zamorano Laura , Juan Carlos , Ge Yigong , Oliver Antonio 
Published: June 2010

ABSTRACTCXA-101, previously designated FR264205, is a new antipseudomonal cephalosporin. The objective of this study was to determine the penicillin-binding protein (PBP) inhibition profile of CXA-101 compared to that of ceftazidime (PBP3 inhibitor) and imipenem (PBP2 inhibitor). Killing kinetics, the induction of AmpC expression, and associated changes on cell morphology were also investigated. The MICs for CXA-101, ceftazidime, and imipenem were 0.5, 1, and 1 μg/ml, respectively. Killing curves revealed that CXA-101 shows a concentration-independent bactericidal activity, with concentrations of 1× the MIC (0.5 μg/ml) producing a >3-log reduction in bacterial load after 8 h of incubation. Live-dead staining showed that concentrations of CXA-101 as low as 0.5× the MIC stopped bacterial septation and induced an intense filamentation, which is consistent with the documented high affinity of PBP3. CXA-101 was found to be a potent PBP3 inhibitor and showed affinities ≥2-fold higher than those of ceftazidime for all of the essential PBPs (1b, 1c, 2, and 3). Compared to imipenem, in addition to the obvious inverse PBP2/PBP3 affinities, CXA-101 showed a significantly higher affinity for PBP1b but a lower affinity for PBP1c. Furthermore, CXA-101, like ceftazidime and in contrast to imipenem, was found to be a very weak inducer of AmpC expression, consistent with the low PBP4 affinity documented.
T-2307 Shows Efficacy in a Murine Model of
Candida glabrata
Infection despite
In Vitro
Trailing Growth Phenomena
Authors: Yamada Eio , Nishikawa Hiroshi , Nomura Nobuhiko , Mitsuyama Junichi 
Published: June 2010

ABSTRACT

T-2307, a novel arylamidine, has been shown to exhibit broad-spectrum
in vitro
and
in vivo
antifungal activities against clinically significant pathogens. In our preliminary studies,
Candida glabrata
exhibited significant trailing growth (partial inhibition of growth over an extended range of antifungal concentrations) in the presence of T-2307 when it was tested using the Clinical and Laboratory Standards Institute (CLSI) guidelines with 0.2% glucose and 48 h of incubation, making reading of the MIC difficult. In the present study, we attempted to attenuate trailing growth to avoid misreading of the MIC. On the basis of the hypothesis that T-2307 may inhibit the mitochondrial functions of cells, the carbon source or the glucose concentration in the medium was changed. The trailing growth of
C. glabrata
ATCC 90030 in the presence of T-2307 was attenuated as the concentration of glucose in the medium decreased to 0.1% or lower, and trailing growth was completely inhibited when glycerol was used. A susceptibility test using Alamar blue was performed to facilitate reading of the MIC without changing the composition of the medium and provided a clear MIC endpoint at 24 h. To investigate if T-2307 shows efficacy against trailing isolates
in vivo
, we evaluated the efficacy of T-2307 in a murine model of disseminated candidiasis caused by
C. glabrata
. T-2307 at 0.05 mg/kg of body weight/day significantly decreased the viable count in the kidneys compared to that for the control group (
P
< 0.05). It would be better to test the susceptibility of
C. glabrata
to T-2307 using modified media or Alamar blue to avoid misreading of the MIC due to the significant trailing growth.
Aerosol Therapy with Colistin Methanesulfonate: a Biopharmaceutical Issue Illustrated in Rats
Authors: Marchand Sandrine , Gobin Patrice , Brillault Julien , Baptista Sara , Adier Christophe , Olivier Jean-Christophe , Mimoz Olivier , Couet William 
Published: June 2010

ABSTRACT

The aim of this study was to evaluate the biopharmaceutical behavior of colistin methanesulfonate (CMS) with special focus on colistin presystemic formation after CMS nebulization in rats. CMS was administered (15 mg·kg
−1
of body weight) either intravenously for systemic pharmacokinetic studies (
n
= 6) or as an intratracheal nebulization for systemic pharmacokinetic studies (
n
= 5) or for CMS and colistin concentration measurements in epithelial lining fluid (ELF) at 30, 120, and 240 min after nebulization (
n
= 14). CMS and colistin concentrations were determined by a new liquid chromatography (LC)-tandem mass spectrometry (MS/MS) assay. Pharmacokinetic parameters were estimated by noncompartmental analysis. CMS and colistin pharmacokinetic data were consistent with previously published values when comparisons were possible. The fraction of the CMS dose converted systematically into colistin after intravenous CMS administration was estimated to be 12.5% on average. After CMS nebulization it was estimated that about two-thirds of the dose was directly absorbed within the systemic circulation, whereas one-third was first converted into active colistin, which was eventually absorbed. As a consequence, the colistin area under curve (AUC) reflecting systemic availability was about 4-fold greater after CMS intratracheal nebulization (607 ± 240 μg·min·ml
−1
) than after CMS intravenous administration (160 ± 20 μg·min·ml
−1
). CMS concentrations in ELF at 30 min and 120 min postnebulization were very high (in the order of several mg/ml) due to the limited volume of ELF but were considerably reduced at 240 min. Although lower (15% ± 5% at 120 min) in relative terms, colistin concentrations in ELF could be high enough for being active against microorganisms following CMS nebulization.
Stereoselective Phosphorylation of Cyclopropavir by pUL97 and Competitive Inhibition by Maribavir
Authors: Gentry Brian G. , Kamil Jeremy P. , Coen Donald M. , Zemlicka Jiri , Drach John C. 
Published: June 2010

ABSTRACT

Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised individuals. Cyclopropavir (CPV) is a guanine nucleoside analog active against human and murine cytomegaloviruses in cell culture and efficacious in mice by oral administration. Previous studies established that the mechanism of action of CPV involves inhibition of viral DNA synthesis. Based upon this action and the structural similarity of CPV to ganciclovir (GCV), we hypothesized that CPV must be phosphorylated to a triphosphate to inhibit HCMV DNA synthesis and that pUL97 is the enzyme responsible for the initial phosphorylation of CPV to a monophosphate (CPV-MP). We found that purified pUL97 phosphorylated CPV 45-fold more extensively than GCV, a known pUL97 substrate and the current standard of treatment for HCMV infections. Kinetic studies with CPV as the substrate for pUL97 demonstrated a

K
m

of 1,750 ± 210 μM. Introduction of 1.0 or 10 nM maribavir, a known pUL97 inhibitor, and subsequent Lineweaver-Burk analysis demonstrated competitive inhibition of CPV phosphorylation, with a

K
i

of 3.0 ± 0.3 nM. Incubation of CPV with pUL97 combined with GMP kinase [known to preferentially phosphorylate the (+)-enantiomer of CPV-MP] established that pUL97 stereoselectively phosphorylates CPV to its (+)-monophosphate. These results elucidate the mechanism of CPV phosphorylation and help explain its selective antiviral action.
Generic Vancomycin Products FailIn Vivodespite Being Pharmaceutical Equivalents of the Innovator
Authors: Vesga Omar , Agudelo Maria , Salazar Beatriz E. , Rodriguez Carlos A. , Zuluaga Andres F. 
Published: June 2010

ABSTRACTGeneric versions of intravenous antibiotics are not required to demonstrate therapeutic equivalence with the innovator because therapeutic equivalence is assumed from pharmaceutical equivalence. To test such assumptions, we studied three generic versions of vancomycin in simultaneous experiments with the innovator and determined the concentration and potency of the active pharmaceutical ingredient by microbiological assay, single-dose pharmacokinetics in infected mice, antibacterial effect by broth microdilution and time-kill curves (TKC), and pharmacodynamics against two wild-type strains ofStaphylococcus aureusby using the neutropenic mouse thigh infection model. The main outcome measure was the comparison of magnitudes and patterns ofin vivoefficacy between generic products and the innovator. Except for one product exhibiting slightly greater concentration, vancomycin generics were undistinguishable from the innovator based on concentration and potency, protein binding,in vitroantibacterial effect determined by minimal inhibitory or bactericidal concentrations and TKC, and serum pharmacokinetics. Despite such similarities, all generic products failedin vivoto killS. aureus, while the innovator displayed the expected bactericidal efficacy: maximum antibacterial effect (Emax) (95% confidence interval [CI]) was 2.04 (1.89 to 2.19), 2.59 (2.21 to 2.98), and 3.48 (2.92 to 4.04) versus 5.65 (5.52 to 5.78) log10CFU/g for three generics and the innovator product, respectively (P< 0.0001, any comparison). Nonlinear regression analysis suggests that generic versions of vancomycin contain inhibitory and stimulatory principles within their formulations that cause agonistic-antagonistic actions responsible forin vivofailure. In conclusion, pharmaceutical equivalence does not imply therapeutic equivalence for vancomycin.
Contribution of BlaA and BlaB β-Lactamases to Antibiotic Susceptibility of
Yersinia enterocolitica
Biovar 1B
Authors: Bent Zachary W. , Young Glenn M. 
Published: June 2010

ABSTRACT

Highly pathogenic
Yersinia enterocolitica
biovar 1B produces two distinct β-lactamases, BlaA and BlaB. Mutants of a representative biovar 1B isolate were constructed and evaluated to determine the extent of limitation of susceptibility to broad-spectrum β-lactam antibiotics by BlaA and BlaB. The results demonstrated that BlaA, a class A enzyme, plays a significant role in limiting susceptibility to penicillins and cephalosporins. The contribution of BlaB, a class C enzyme, was less profound and was limited primarily to cephalosporin susceptibility.
Translocation of
Porphyromonas gingivalis
Gingipain Adhesin Peptide A44 to Host Mitochondria Prevents Apoptosis
Authors: Boisvert Heike , Duncan Margaret J. 
Published: June 2010

ABSTRACT

Porphyromonas gingivalis
, a Gram-negative oral anaerobe, is associated with periodontal diseases that, in some form, affect up to 80% of the U.S. population. The organism is highly proteolytic, and noncatalytic adhesin domains of the major proteases, gingipains, are involved in bacterium-host interactions. Recently, we showed that gingipain adhesin peptide A44 hijacks the host's clathrin-dependent endocytosis system, allowing the peptide and whole bacteria to be internalized by epithelial cells. In the present study, we found by cell fractionation assays and confocal microscopy that peptide A44 translocated to host mitochondria. Cell viability assays and quantitative real-time PCR showed that the peptide interacted with the cell death machinery by triggering upregulation of antiapoptotic factors
bcl-2
and
bcl-XL
and prevented staurosporine-induced apoptosis for up to 12 h. We confirmed these findings with Western blot analyses of caspase-9 activation in time course experiments with staurosporine. Finally, we verified a similar antiapoptotic effect for
P. gingivalis
, showing for the first time that the organism manipulated mitochondrial functions during the first hours of infection, thus resisting host cell clearance by apoptosis of infected cells. This mechanism may enable the bacteria to persist in the protected cellular environment until the next step in pathogenesis, progression or resolution of infection.