bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accumulation and Intracellular Distribution of Antitrypanosomal Diamidine Compounds DB75 and DB820 in African Trypanosomes
Authors: Mathis Amanda M. , Holman Jacqueline L. , Sturk Lisa M. , Ismail Mohamed A. , Boykin David W. , Tidwell Richard R. , Hall James Edwin 
Published: May 2006

ABSTRACT
The aromatic diamidine pentamidine has long been used to treat early-stage human African trypanosomiasis (HAT). Two analogs of pentamidine, DB75 and DB820, have been shown to be more potent and less toxic than pentamidine in murine models of trypanosomiasis. The diphenyl furan diamidine, DB75, is the active metabolite of the prodrug DB289, which is currently in phase III clinical trials as a new orally active candidate drug to treat first-stage HAT. The new aza analog, DB820, is the active diamidine of the prodrug DB844, currently undergoing preclinical evaluation as a new candidate to treat HAT of the central nervous system. The exact mechanisms of antitrypanosomal activity of aromatic dications remain poorly understood, with multiple mechanisms hypothesized. Pentamidine is known to be actively transported into trypanosomes and binds to DNA within the nucleus and kinetoplast. A long-hypothesized mechanism of action has been that DNA binding ultimately leads to interference with DNA-associated enzymes. Both DB75 and DB820 are intensely fluorescent, which provides an important tool for determining the kinetics of accumulation and intracellular distribution in trypanosomes. We show in the current study that DB75 and DB820 rapidly accumulate and strongly concentrate within trypanosomes, with intracellular concentrations over 15,000-fold higher than mouse plasma concentrations. Both compounds initially accumulate in the DNA-containing nucleus and kinetoplast, but at later time points, they concentrate in non-DNA-containing cytoplasmic organelles. Analyses of the kinetics of uptake and intracellular distribution are necessary to begin to define antitrypanosomal mechanisms of action of DB75, DB820, and other aromatic diamidines.
Novel Conjugate of Moxifloxacin and Carboxymethylated Glucan with Enhanced Activity againstMycobacterium tuberculosis
Authors: Schwartz Y. S. , Dushkin M. I. , Vavilin V. A. , Melnikova E. V. , Khoschenko O. M. , Kozlov V. A. , Agafonov A. P. , Alekseev A. Y. , Rassadkin Y. , Shestapalov A. M. , Azaev M. S. , Saraev D. V. , Filimonov P. N. , Kurunov Y. , Svistelnik A. V. , Krasnov V. A. , Pathak A. , Derrick S. C. , Reynolds R. C. , Morris S. , Blinov V. M. 
Published: May 2006

ABSTRACTMycobacterium tuberculosisis an intracellular pathogen that persists within macrophages of the human host. One approach to improving the treatment of tuberculosis (TB) is the targeted delivery of antibiotics to macrophages using ligands to macrophage receptors. The moxifloxacin-conjugated dansylated carboxymethylglucan (M-DCMG) conjugate was prepared by chemically linking dansylcadaverine (D) and moxifloxacin (M) to carboxymethylglucan (CMG), a known ligand of macrophage scavenger receptors. The targeted delivery to macrophages and the antituberculosis activity of the conjugate M-DCMG were studied in vitro and in vivo. Using fluorescence microscopy, fluorimetry, and the J774 macrophage cell line, M-DCMG was shown to accumulate in macrophages through scavenger receptors in a dose-dependent (1 to 50 μg/ml) manner. After intravenous administration of M-DCMG into C57BL/6 mice, the fluorescent conjugate was concentrated in the macrophages of the lungs and spleen. Analyses of the pharmacokinetics of the conjugate demonstrated that M-DCMG was more rapidly accumulated and more persistent in tissues than free moxifloxacin. Importantly, therapeutic studies of mycobacterial growth in C57BL/6 mice showed that the M-DCMG conjugate was significantly more potent than free moxifloxacin.
Detection of Live and Antibiotic-Killed Bacteria by Quantitative Real-Time PCR of Specific Fragments of rRNA
Authors: Aellen Steve , Que Yok-Ai , Guignard Bertrand , Haenni Marisa , Moreillon Philippe 
Published: May 2006

ABSTRACT

Assessing bacterial viability by molecular markers might help accelerate the measurement of antibiotic-induced killing. This study investigated whether rRNA could be suitable for this purpose. Cultures of penicillin-susceptible and penicillin-tolerant (Tol1 mutant)
Streptococcus gordonii
were exposed to mechanistically different penicillin and levofloxacin. Bacterial survival was assessed by viable counts and compared to quantitative real-time PCR amplification of either the 16S rRNA genes or the 16S rRNA, following reverse transcription. Penicillin-susceptible
S. gordonii
lost ≥4 log
10
CFU/ml of viability over 48 h of penicillin treatment. In comparison, the Tol1 mutant lost ≤1 log
10
CFU/ml. Amplification of a 427-bp fragment of 16S rRNA genes yielded amplicons that increased proportionally to viable counts during bacterial growth but did not decrease during drug-induced killing. In contrast, the same 427-bp fragment amplified from 16S rRNA paralleled both bacterial growth and drug-induced killing. It also differentiated between penicillin-induced killing of the parent and the Tol1 mutant (≥4 log
10
CFU/ml and ≤1 log
10
CFU/ml, respectively) and detected killing by mechanistically unrelated levofloxacin. Since large fragments of polynucleotides might be degraded faster than smaller fragments, the experiments were repeated by amplifying a 119-bp region internal to the original 427-bp fragment. The amount of 119-bp amplicons increased proportionally to viability during growth but remained stable during drug treatment. Thus, 16S rRNA was a marker of antibiotic-induced killing, but the size of the amplified fragment was critical for differentiation between live and dead bacteria.
Idebenone Acts against Growth of
Helicobacter pylori
by Inhibiting Its Respiration
Authors: Inatsu Sakiko , Ohsaki Ayumi , Nagata Kumiko 
Published: May 2006

ABSTRACT

Growth of
Helicobacter pylori
was inhibited by the quinones, idebenone, duroquinone, menadione, juglone, and coenzyme Q
1
at low concentrations of 0.8 to 3.2 μg/ml. Idebenone specifically inhibited
H. pylori
growth by inhibiting respiration and decreasing the cellular ATP level. The respiratory inhibition was accompanied by reduction of idebenone by the
H. pylori
cells.
Effect of Culture Medium on the Disk Diffusion Method for Determining Antifungal Susceptibilities of Dermatophytes
Authors: Fernández-Torres Belkys , Carrillo-Muñoz Alfonso , Inza Isabel , Guarro Josep 
Published: May 2006

ABSTRACT
We have evaluated a disk diffusion method to determine the activities of five drugs against 50 strains of dermatophytes and to assess the influence of the culture medium (antibiotic medium 3, high-resolution medium, and RPMI) on the inhibition zone diameters (IZD). There were no differences among the medium/drug combinations, except for itraconazole-RPMI, which showed the narrowest IZD.
Levofloxacin Pharmacokinetics and Pharmacodynamics in Patients with Severe Burn Injury
Authors: Kiser Tyree H. , Hoody Dorie W. , Obritsch Marilee D. , Wegzyn Colleen O. , Bauling Paulus C. , Fish Douglas N. 
Published: May 2006

ABSTRACT

Levofloxacin pharmacokinetics were studied in 11 patients with severe burn injuries. Patients (values are means ± standard deviations; age, 41 ± 17 years; weight, 81 ± 12 kg; creatinine clearance, 114 ± 40 ml/min) received intravenous levofloxacin at 750 mg (
n
= 10 patients) or 500 mg (
n
= one patient) once daily. Blood samples were collected on day 1 of levofloxacin therapy; eight patients were studied again on days 4 to 6. The pharmacodynamic probability of target attainment (PTA) was evaluated by Monte Carlo simulation. Mean systemic clearance, half-life, and area under the concentration-time curve over 24 h after levofloxacin at 750 mg were 9.0 ± 3.2 liters/h, 7.8 ± 1.6 h, and 93 ± 31 mg · h/liter, respectively. There were no differences in pharmacokinetic parameters between day 1 and day 4; however, large intrapatient and interpatient variability was observed. Levofloxacin pharmacokinetics in burned patients were similar to those reported in other critically ill populations. Levofloxacin at 750 mg achieved >90% PTA for gram-negative and gram-positive pathogens with MICs of ≤0.5 μg/ml and MICs of ≤1 μg/ml, respectively. However, satisfactory PTA was not obtained with less-susceptible gram-negative organisms with MICs of 1 μg/ml or any organism with a MIC of ≥2 μg/ml. The results of this study indicate that levofloxacin should be administered at 750 mg/day for treatment of systemic infections in severely burned patients. However, even 750 mg/day may be inadequate for gram-negative organisms with MICs of 1 to 2 μg/ml even though they are defined as susceptible. Alternative antibiotics or treatment strategies should be considered for infections due to these pathogens.
Efficacy of Macrolides and Telithromycin against Leptospirosis in a Hamster Model
Authors: Moon James E. , Ellis Michael C. , Griffith Matthew E. , Hawley Joshua S. , Rivard Robert G. , McCall Suzanne , Hospenthal Duane R. , Murray Clinton K. 
Published: May 2006

ABSTRACTHuman studies support the use of β-lactams and tetracyclines in the treatment of leptospirosis. Additional agents from these and other classes of antimicrobials also have in vitro activity againstLeptospiraspecies, though corroborating in vivo data are limited or lacking. We evaluated the therapeutic efficacy of azithromycin, clarithromycin, and telithromycin in a lethal hamster model of leptospirosis usingLeptospira interrogansserogroup Canicola serovar Portlandvere. A range of dosages for each antimicrobial was given to the infected animals on days 2 through 7 (5 days) of the 21-day survival model. All untreated control animals survived less than 10 days from infection. Ninety to 100% of doxycycline controls, treated for 5 days with 5 mg/kg of body weight of drug, survived to 21 days. Treatment with azithromycin (daily dose: 6.25, 12.5, 25, 50, 100, or 200 mg/kg) resulted in 100% survival at all evaluated doses. Animals receiving 20 mg/kg or more of clarithromycin (daily dose: 1, 5, 10, 15, 20, 40, 60, or 100 mg/kg) had improved survival. Ninety-eight percent of animals treated with telithromycin (daily dose: 1, 5, 10, 15, 20, or 40 mg/kg) survived. We conclude that all agents tested have demonstrated in vivo efficacy in treating acute leptospirosis. These results provide support for further evaluation of macrolide and ketolide antimicrobial agents in human trials.
Transmission-Blocking Activities of Quinine, Primaquine, and Artesunate
Authors: Chotivanich Kesinee , Sattabongkot Jetsumon , Udomsangpetch Rachanee , Looareesuwan Sornchai , Day Nicholas P. J. , Coleman Russell E. , White Nicholas J. 
Published: May 2006

ABSTRACT

The infectivity of
Plasmodium falciparum
gametocytes after exposure in vitro to quinine, artesunate, and primaquine was assessed in
Anopheles dirus
, a major vector of malaria in Southeast Asia. Mature gametocytes (stage 5) of a Thai isolate of
P. falciparum
were exposed to the drugs for 24 h in vitro before membrane feeding to
A. dirus
. After 10 days, the mosquito midguts were dissected and the oocysts were counted. In this system, artesunate showed the most potent transmission-blocking activity; the mean (standard deviation [SD]) 50% and 90% effective concentrations (EC
50
, and EC
90
, respectively, in nanograms per milliliter) were 0.1 (0.02) and 0.4 (0.15), respectively. Transmission-blocking activity of quinine and primaquine was observed at relatively high concentrations (SDs): EC
50
of quinine, 642 (111) ng/ml; EC
50
of primaquine, 181 (23) ng/ml; EC
90
of quinine, 816 (96) ng/ml; EC
90
of primaquine, 543 (43) ng/ml. Artesunate both prevents the maturation of immature
P. falciparum
gametocytes and reduces the transmission potential of mature gametocytes. Both of these effects may contribute to reducing malaria transmission.
Effects of the Antifungals Voriconazole and Fluconazole on the Pharmacokinetics ofS-(+)- andR-(−)-Ibuprofen
Authors: Hynninen Ville-Veikko , Olkkola Klaus T. , Leino Kari , Lundgren Stefan , Neuvonen Pertti J. , Rane Anders , Valtonen Mika , Vyyryläinen Hanna , Laine Kari 
Published: May 2006

ABSTRACTOur objective was to study the effects of the antifungals voriconazole and fluconazole on the pharmacokinetics ofS-(+)- andR-(−)-ibuprofen. Twelve healthy male volunteers took a single oral dose of 400 mg racemic ibuprofen in a randomized order either alone, after ingestion of voriconazole at 400 mg twice daily on the first day and 200 mg twice daily on the second day, or after ingestion of fluconazole at 400 mg on the first day and 200 mg on the second day. Ibuprofen was ingested 1 h after administration of the last dose of voriconazole or fluconazole. Plasma concentrations ofS-(+)- andR-(−)-ibuprofen were measured for up to 24 h. In the voriconazole phase, the mean area under the plasma concentration-time curve (AUC) ofS-(+)-ibuprofen was 205% (P< 0.001) of the respective control value and the mean peak plasma concentration (Cmax) was 122% (P< 0.01) of the respective control value. The mean elimination half-life (t1/2) was prolonged from 2.4 to 3.2 h (P< 0.01) by voriconazole. In the fluconazole phase, the mean AUC ofS-(+)-ibuprofen was 183% of the control value (P< 0.001) and its meanCmaxwas 116% of the control value (P< 0.05). The meant1/2ofS-(+)-ibuprofen was prolonged from 2.4 to 3.1 h (P< 0.05) by fluconazole. The geometric meanS-(+)-ibuprofen AUC ratios in the voriconazole and fluconazole phases were 2.01 (90% confidence interval [CI], 1.80 to 2.22) and 1.82 (90% CI, 1.72 to 1.91), respectively, i.e., above the bioequivalence acceptance upper limit of 1.25. Voriconazole and fluconazole had only weak effects on the pharmacokinetics ofR-(−)-ibuprofen. In conclusion, voriconazole and fluconazole increased the levels of exposure toS-(+)-ibuprofen 2- and 1.8-fold, respectively. This was likely caused by inhibition of the cytochrome P450 2C9-mediated metabolism ofS-(+)-ibuprofen. A reduction of the ibuprofen dosage should be considered when ibuprofen is coadministered with voriconazole or fluconazole, especially when the initial ibuprofen dose is high.
Single-Dose Safety and Pharmacokinetics of Brecanavir, a Novel Human Immunodeficiency Virus Protease Inhibitor
Authors: Ford Susan L. , Reddy Y. Sunila , Anderson Maggie T. , Murray Sharon C. , Fernandez Pedro , Stein Daniel S. , Johnson Mark A. 
Published: May 2006

ABSTRACT
Brecanavir (BCV, 640385) is a novel, potent protease inhibitor (PI) with low nanomolar 50% inhibitory concentrations against PI-resistant human immunodeficiency virus (HIV) in vitro. This phase I, double-blind, randomized, placebo-controlled, two-part single-dose study (first time with humans) was conducted to determine the safety, tolerability, and pharmacokinetics of BCV administered at 10 mg/ml in a tocopherol-polyethylene glycol succinate-polyethylene glycol 400-ethanol 50:40:10 solution. In part 1 of the study, single oral doses of BCV ranged from 25 mg to 800 mg. In part 2, single oral doses of BCV ranged from 10 mg to 300 mg and were coadministered with 100-mg oral ritonavir (RTV) soft gel capsules. Single doses of BCV and BCV/RTV were generally well tolerated. There were no severe adverse events (SAEs), and no subject was withdrawn due to BCV. The most commonly reported drug-related AEs during both parts of the study combined were gastrointestinal disturbances (similar to placebo) and headache. BCV was readily absorbed following oral administration with mean times to maximum concentration from >1 h to 2.5 h in part 1 and from 1.5 h to 3 h in part 2. Administration of BCV without RTV resulted in BCV exposures predicted to be insufficient to inhibit PI-resistant virus based on in vitro data. Coadministration of 300 mg BCV with 100 mg RTV, however, significantly increased the plasma BCV area under the concentration-time curve and maximum concentration 26-fold and 11-fold, respectively, achieving BCV concentrations predicted to inhibit PI-resistant HIV.
Functional, Biophysical, and Structural Bases for Antibacterial Activity of Tigecycline
Authors: Olson Matthew W. , Ruzin Alexey , Feyfant Eric , Rush Thomas S. , O'Connell John , Bradford Patricia A. 
Published: May 2006

ABSTRACT

Tigecycline is a novel glycylcycline antibiotic that possesses broad-spectrum activity against many clinically relevant species of bacterial pathogens. The mechanism of action of tigecycline was delineated using functional, biophysical, and molecular modeling experiments in this study. Functional assays showed that tigecycline specifically inhibits bacterial protein synthesis with potency 3- and 20-fold greater than that of minocycline and tetracycline, respectively. Biophysical analyses demonstrated that isolated ribosomes bind tigecycline, minocycline, and tetracycline with dissociation constant values of 10
−8
, 10
−7
, and >10
−6
M, respectively. A molecular model of tigecycline bound to the ribosome was generated with the aid of a 3.40-angstrom resolution X-ray diffraction structure of the 30S ribosomal subunit from
Thermus thermophilus
. This model places tigecycline in the A site of the 30S subunit and involves substantial interactions with residues of H34 of the ribosomal subunit. These interactions were not observed in a model of tetracycline binding. Modeling data were consistent with the biochemical and biophysical data generated in this and other recent studies and suggested that tigecycline binds to bacterial ribosomes in a novel way that allows it to overcome tetracycline resistance due to ribosomal protection.
Persistence of
Mycoplasma hyopneumoniae
in Experimentally Infected Pigs after Marbofloxacin Treatment and Detection of Mutations in the
parC
Gene
Authors: Le Carrou J. , Laurentie M. , Kobisch M. , Gautier-Bouchardon A. V. 
Published: May 2006

ABSTRACT

The ability of
Mycoplasma hyopneumoniae
to persist despite fluoroquinolone treatments was investigated with pigs. Groups of specific-pathogen-free pigs were experimentally infected with
M. hyopneumoniae
strain 116 and treated with marbofloxacin at the therapeutic dose (TD) or half of the therapeutic dose (TD/2) for 3 days. Results showed that, despite tissue penetration of marbofloxacin, particularly in the trachea and the tracheal secretions, the treatments did not have any influence on
M. hyopneumoniae
recovery from tracheal swabs. Mycoplasmas were also isolated from inner organs and tissues such as liver, spleen, kidneys, and bronchial lymph nodes. Recontamination of pigs via environment could not explain mycoplasma persistence after medication, as decontamination of pigs and allocation to a new disinfected environment did not have any significant effect on the phenomenon. A significant decrease in the susceptibility level to marbofloxacin of 12 mycoplasma clones reisolated after the treatments (TD/2 and TD) was observed. Two point mutations were found in the ParC quinolone resistance-determining region (QRDR) of DNA topoisomerase IV (Ser80→Phe and Asp84→Asn), and one point mutation was observed just behind the QRDR of ParC (Ala116→Glu). This is the first time that mutations in a gene coding for topoisomerase IV have been described for
M. hyopneumoniae
after in vivo marbofloxacin treatments in experimentally infected pigs. However, development of resistance is not sufficient to explain
M. hyopneumoniae
persistence in vivo since (i) marbofloxacin concentrations were above the marbofloxacin MIC of the wild-type strain and (ii) mycoplasmas reisolated after a single injection of marbofloxacin did not display an increased marbofloxacin MIC.
VanG-Type Vancomycin-Resistant
Enterococcus faecalis
Strains Isolated in Canada
Authors: Boyd David A. , Du Tim , Hizon Romeo , Kaplen Brynn , Murphy Travis , Tyler Shaun , Brown Shirley , Jamieson Frances , Weiss Karl , Mulvey Michael R. ,   the Canadian Nosocomial Infection Surveillance Program
Published: May 2006

ABSTRACT

Enterococcus faecalis
G1-0247 (vancomycin MIC, 16 μg/ml) was found to harbor a
vanG
operon 99% identical to the
vanG
operon in
E. faecalis
BM4518.
E. faecalis
N03-0233 (vancomycin MIC, 16 μg/ml) was found to harbor a novel
vanG
operon,
vanG2
, on an element in a different chromosomal location than the
vanG
-harboring elements in G1-0247 and BM4518.
Inhibition of Human Coronavirus NL63 Infection at Early Stages of the Replication Cycle
Authors: Pyrc Krzysztof , Bosch Berend Jan , Berkhout Ben , Jebbink Maarten F. , Dijkman Ronald , Rottier Peter , van der Hoek Lia 
Published: May 2006

ABSTRACT

Human coronavirus NL63 (HCoV-NL63), a recently discovered member of the
Coronaviridae
family, has spread worldwide and is associated with acute respiratory illness in young children and elderly and immunocompromised persons. Further analysis of HCoV-NL63 pathogenicity seems warranted, in particular because the virus uses the same cellular receptor as severe acute respiratory syndrome-associated coronavirus. As there is currently no HCoV-NL63-specific and effective vaccine or drug therapy available, we evaluated several existing antiviral drugs and new synthetic compounds as inhibitors of HCoV-NL63, targeting multiple stages of the replication cycle. Of the 28 compounds that we tested, 6 potently inhibited HCoV-NL63 at early steps of the replication cycle. Intravenous immunoglobulins, heptad repeat 2 peptide, small interfering RNA1 (siRNA1), siRNA2, β-
d
-N
4
-hydroxycytidine, and 6-azauridine showed 50% inhibitory concentrations of 125 μg/ml, 2 μM, 5 nM, 3 nM, 400 nM, and 32 nM, respectively, and low 50% cytotoxicity concentrations (>10 mg/ml, >40 μM, >200 nM, >200 nM, >100 μM, and 80 μM, respectively). These agents may be investigated further for the treatment of coronavirus infections.
Biological, Biochemical, and Molecular Characterization of a New Clinical
Trichophyton rubrum
Isolate Resistant to Terbinafine
Authors: Osborne Colin S. , Leitner Ingrid , Hofbauer Bettina , Fielding Ceri A. , Favre Bertrand , Ryder Neil S. 
Published: May 2006

ABSTRACT

We have characterized a new clinical strain of
Trichophyton rubrum
highly resistant to terbinafine but exhibiting normal susceptibility to drugs with other mechanisms of action. Resistance to terbinafine in this strain is caused by a missense mutation in the squalene epoxidase gene leading to the amino acid substitution F397L.
"Women Behaving Badly": Crime, Transgressive Behaviour and Gender In Early Twentieth Century China
Authors: Bailey Paul 
Published: May 2006

AbstractThis article analyses a critical discourse on women that was pervasive in an emerging newspaper and periodical press during the last years of the Qing dynasty and early years of the Republic, at a time when governing and intellectual elites were becoming increasingly obsessed with 'behavioural modernization'. This critical discourse reflected anxieties concerning the pace and direction of social and cultural change, as well as ambivalence about women's growing public visibility. At the same time, such a discourse provides an insight into how adolescent girls and women responded to new opportunities in the public sphere before the May Fourth Movement, and clearly shows they did not always behave in ways prescribed by officials, educators and intellectuals.