bluuebunny/crossref_metadata_2025_split huggingface dataset:
2,4-Diaminopteridine-Based Compounds as Precursors for De Novo Synthesis of Antifolates: a Novel Class of Antimalarials
Authors: Nduati Eunice , Hunt Sonya , Kamau Eddy M. , Nzila Alexis 
Published: August 2005

ABSTRACTWe have tested the hypothesis that 2,4-diamino-6-hydroxymethyl-pteridine (DAP), 2,4-diaminopteroic acid (DAPA), and 2,4 diamino-N10-methyl-pteroic acid (DAMPA) could be converted into aminopterin (from DAP and DAPA) and methotrexate (from DAMPA), both of which are potent inhibitors of dihydrofolate reductase, a proven drug target forPlasmodium falciparum. DAP, DAPA, and DAMPA inhibited parasite growth in the micromolar range; DAMPA was the most active, with 50% inhibitory concentrations in vitro of 446 ng/ml against the antifolate-sensitive strain and 812 ng/ml against the highly resistant strain under physiological folate conditions. DAMPA potentiates the activity of the sulfone dapsone, an inhibitor of dihydropteroate synthase, but not that of chlorcycloguanil, a known inhibitor of dihydrofolate reductase (DHFR). Experiments with aSaccharomyces cerevisiaestrain dependent upon theP. falciparumDHFR enzyme showed that DHFR is a target of DAMPA in that system. We hypothesize that DAMPA is converted to methotrexate by the parasite dihydrofolate synthase, which explains the synergy of DAMPA with dapsone but not with chlorcycloguanil. This de novo synthesis will not occur in the host, since it lacks the complete folate pathway. If this hypothesis holds true, the de novo synthesis of the toxic compounds could be used as a framework for the search for novel potent antimalarial antifolates.
Quinine Pharmacokinetics and Pharmacodynamics in Children with Malaria Caused by
Plasmodium falciparum
Authors: Le Jouan M. , Jullien V. , Tetanye E. , Tran A. , Rey E. , Tréluyer J.-M. , Tod M. , Pons G. 
Published: August 2005

ABSTRACT

The aim of the present study was to assess the pharmacokinetics and the efficacy of a shorter than usual 5-day quinine treatment given orally to children in Cameroon with malaria caused by
Plasmodium falciparum
. Quinine (8.3 mg of base per kg of body weight every 8 h) was administered as a 2% formiate salt syrup for 5 days to 30 children (age range, 0.55 to 6.7 years) with uncomplicated falciparum malaria (initial parasitemia, 1.4 × 10
3
to 1.8 × 10
5
/μl). Quinine concentrations in plasma samples (five to nine per patient) were measured by liquid chromatography on days 1 to 3. Parasitemia was counted on days 0, 1, 2, 3, 4, 7, and 14. Pharmacokinetic and pharmacodynamic data were analyzed by population approaches by using NONMEM and WinBugs, respectively. The kinetics of quinine were best described by a one-compartment model with time-varying protein binding. Clearance and the volume of distribution were positively correlated with body weight and increased over time. Parasitemia was undetectable from day 3 to 14 in all children. The time to a 4-log reduction of the initial level of parasitemia (
T
er
) was related to the average quinine concentration from 0 to 72 h (
C
av
) as
T
er
=
T
min
[1 + (
C
50
/
C
av
)

s

], where sigmoidicity (
s
) is equal to 2,
T
min
is the time to eradication at infinite
C
av
, and
C
50
is the value of
C
av
for which
T
er
is twice
T
min
. The
C
50
distribution was unimodal, and all
C
50
values were less than 8 mg/liter, while
C
av
ranged from 5.9 to 18.3 mg/liter. The median (10th to 90th percentile)
T
er
was 47 h (range, 39 to 76 h). The efficacy of a 5-day treatment course should be evaluated in a larger clinical trial.
Absolute Bioavailability and Pharmacokinetics of Linezolid in Hospitalized Patients Given Enteral Feedings
Authors: Beringer Paul , Nguyen Megan , Hoem Nils , Louie Stan , Gill Mark , Gurevitch Michael , Wong-Beringer Annie 
Published: August 2005

ABSTRACTLinezolid is a new antimicrobial agent effective against drug-resistant gram-positive pathogens which are common causes of infections in hospitalized patients. Many such patients rely on the intravenous or enteral route for nutrition and drug administration. Therefore, the bioavailability of linezolid administered enterally in the presence of enteral feedings in hospitalized patients was examined. Eighteen subjects were assessed in a randomized single-dose crossover study; 12 received continuous enteral feedings, while 6 did not (controls). Both groups received linezolid 600 mg intravenously and orally (control) or enterally, with the alternate route of administration separated by a 24-h washout period. Pharmacokinetic parameters derived from noncompartmental and compartmental analysis incorporating linear and nonlinear elimination pathways were compared between groups:F,Ka,Vs,K23,K32,Vmax,Km, andK20(bioavailability, absorption rate constant, volume of central compartment normalized to body weight, intercompartmental rate constants, maximum velocity, Michaelis-Menten constant, and elimination rate constant, respectively). Pharmacokinetic (PK) data were available from 17 patients. The linezolid oral suspension was rapidly and completely absorbed by either the oral or enteral route of administration. Bioavailability was unaltered in the presence of enteral feedings. PK estimates remain similar regardless of the model applied. At the therapeutic dose used, only slight nonlinearity in elimination was observed. A linezolid oral suspension may be administered via the enteral route to hospitalized patients without compromise in its excellent bioavailability and rapid rate of absorption. Compartmental pharmacokinetic analysis offers a more flexible study application, since bioavailability (F) can be estimated directly with intermixed intravenous/oral doses without a need for a washout period.
Purine Nucleobase Transport in Amastigotes of
Leishmania mexicana
: Involvement in Allopurinol Uptake
Authors: Al-Salabi Mohammed I. , de Koning Harry P. 
Published: August 2005

ABSTRACT

Nucleobase and nucleoside transporters play central roles in the biochemistry of parasitic protozoa, as they lack the ability to synthesize purines de novo and are absolutely reliant upon purine salvage from their hosts. Furthermore, such transporters are potentially critical to the pharmacology of these important human pathogens, because they mediate the uptake of purine analogues, as well as some nonpurine drugs, that can be selectively cytotoxic to the parasites. We here report the first identification and characterization of a purine nucleobase transporter in
Leishmania
amastigotes. Uptake of [
3
H]hypoxanthine by
Leishmania mexicana
amastigotes was mediated by a single high-affinity transporter, LmexNBT1, with a

K
m

of 1.6 ± 0.4 μM and high affinity for adenine, guanine, and xanthine but low affinity for nucleosides and pyrimidine nucleobases. Allopurinol, an antileishmanial hypoxanthine analogue, was apparently taken up by the same transporter. Using [
3
H]allopurinol, a

K
m

value of 33.6 ± 6.0 μM was obtained. All evidence was compatible with a model of a single purine nucleobase transporter being expressed in amastigotes. Using various purine nucleobase analogues, a model for the interactions between hypoxanthine and the transporter's permeant binding site was constructed. The binding interactions were compared with those of the LmajNBT1 transporter in
Leishmania major
promastigotes and found to be very similar.
Development of a Novel Targeting System for Lethal Photosensitization of Antibiotic-Resistant Strains of
Staphylococcus aureus
Authors: Embleton Michelle L. , Nair Sean P. , Heywood Wendy , Menon Dev C. , Cookson Barry D. , Wilson Michael 
Published: August 2005

ABSTRACT

Light-activated antimicrobial agents (photosensitizers) are promising alternatives to antibiotics for the treatment of topical infections. To improve efficacy and avoid possible damage to host tissues, targeting of the photosensitizer to the infecting organism is desirable, and this has previously been achieved using antibodies and chemical modification of the agent. In this study we investigated the possibility of using a bacteriophage to deliver the photosensitizer tin(IV) chlorin e6 (SnCe6) to
Staphylococcus aureus
. SnCe6 was covalently linked to
S. aureus
bacteriophage 75, and the ability of the conjugate to kill various strains of
S. aureus
when exposed to red light was determined. Substantial kills of methicillin- and vancomycin-intermediate strains of
S. aureus
were achieved using low concentrations of the conjugate (containing 1.5 μg/ml SnCe6) and low light doses (21 J/cm
2
). Under these conditions, the viability of human epithelial cells (in the absence of bacteria) was largely unaffected. On a molar equivalent basis, the conjugate was a more effective bactericide than the unconjugated SnCe6, and killing was not growth phase dependent. The conjugate was effective against vancomycin-intermediate strains of
S. aureus
even after growth in vancomycin. The results of this study have demonstrated that a bacteriophage can be used to deliver a photosensitizer to a target organism, resulting in enhanced and selective killing of the organism. Such attributes are desirable in an agent to be used in the photodynamic therapy of infectious diseases.
Pharmacokinetic Modeling of Free Amoxicillin Concentrations in Rat Muscle Extracellular Fluids Determined by Microdialysis
Authors: Marchand Sandrine , Chenel Marylore , Lamarche Isabelle , Couet William 
Published: August 2005

ABSTRACT

The aim of the present study was to investigate amoxicillin (AMX) distribution in muscle interstitial fluid by microdialysis in healthy, awake rats. Microdialysis probes were inserted into the jugular vein and hind leg muscle. Probe recoveries in each rat were determined by retrodialysis with cefadroxil. AMX was administered as a bolus dose of 50 mg · kg
−1
, and microdialysis samples were collected during 180 min. Concentrations of unbound drug in blood and muscle were analyzed simultaneously by a population approach. Simulations were conducted using a hybrid, physiologically based pharmacokinetic model to investigate the potential impact of tissue blood flow on muscle AMX distribution. A two-compartment pharmacokinetic model described adequately the unbound amoxicillin concentration-time profiles in blood and muscle. Muscle AMX distribution equilibrium was rapidly achieved. Consequently, the best results were obtained by considering concentrations in muscle as part of the central compartment. The ratio of the concentration of unbound drug in muscle to that in blood (
R
model
) was estimated to 0.80 by the model, which is close to the mean value obtained by noncompartmental data analysis (
R
area
= 0.86 ± 0.29). Simulations conducted with a hybrid, physiologically based pharmacokinetic model suggest that a muscle blood flow reduction of 30% to 50%, such as could be encountered in critical care patients, has virtually no effect on muscle AMX concentration profiles. In conclusion, this study has clearly demonstrated that AMX distributes rapidly and extensively within muscle interstitial fluid, consistent with theory, and that altered muscle blood flow seems unlikely to have a major effect on these distribution characteristics.
In Vitro Efficacies of Nitazoxanide and Other Thiazolides againstNeospora caninumTachyzoites Reveal Antiparasitic Activity Independent of the Nitro Group
Authors: Esposito Marco , Stettler Rebecca , Moores Shelley L. , Pidathala Chandrakala , Müller Norbert , Stachulski Andrew , Berry Neil G. , Rossignol Jean-Francois , Hemphill Andrew 
Published: August 2005

ABSTRACTThe thiazolide nitazoxanide [2-acetolyloxy-N-(5-nitro-2-thiazolyl)benzamide] (NTZ) exhibits a broad spectrum of activities against a wide variety of intestinal and tissue-dwelling helminths, protozoa, and enteric bacteria infecting animals and humans. The drug has been postulated to act via reduction of its nitro group by nitroreductases, including pyruvate ferredoxin oxidoreductase. In this study, we investigated the efficacies of nitazoxanide and a number of other thiazolides againstNeospora caninumtachyzoites in vitro. We employed real-time-PCR-based monitoring of tachyzoite adhesion, invasion, and intracellular proliferation, as well as electron microscopic visualization of the effects imposed by nitazoxanide. In addition, we investigated several modified versions of this drug. These modifications included on one hand the replacement of the nitro group on the thiazole ring with a bromide, thus removing the most reactive group, and on the other hand the differential positioning of methyl groups on the salicylate ring. We show that the thiazole-associated nitro group is not necessarily required for the action of the drug and that methylation of the salicylate ring can result in complete abrogation of the antiparasitic activity, depending on the positioning of the methyl group. These findings indicate that other mechanisms besides the proposed mode of action involving the pyruvate ferredoxin oxidoreductase enzyme could be responsible for the wide spectrum of antiparasitic activity of NTZ and that modifications in the benzene ring could be important in these alternative mechanisms.
Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro
Authors: Williams-Aziz Stephanie L. , Hartline Caroll B. , Harden Emma A. , Daily Shannon L. , Prichard Mark N. , Kushner Nicole L. , Beadle James R. , Wan W. Brad , Hostetler Karl Y. , Kern Earl R. 
Published: August 2005

ABSTRACT

Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 μM reduced herpesvirus replication by 50% (EC
50
) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC
50
values of the lipid esters were at least 100-fold lower than the EC
50
values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.
Design of a Small-Molecule Entry Inhibitor with Activity against Primary Measles Virus Strains
Authors: Plemper Richard K. , Doyle Joshua , Sun Aiming , Prussia Andrew , Cheng Li-Ting , Rota Paul A. , Liotta Dennis C. , Snyder James P. , Compans Richard W. 
Published: August 2005

ABSTRACT
The incidence of measles virus (MV) infection has been significantly reduced in many nations through extensive vaccination; however, the virus still causes significant morbidity and mortality in developing countries. Measles outbreaks also occur in some developed countries that have failed to maintain high vaccine coverage rates. While vaccination is essential in preventing the spread of measles, case management would greatly benefit from the use of therapeutic agents to lower morbidity. Thus, the development of new therapeutic strategies is desirable. We previously reported the generation of a panel of small-molecule MV entry inhibitors. Here we show that our initial lead compound, although providing proof of concept for our approach, has a short half-life (<16 h) under physiological conditions. In order to combine potent antiviral activity with increased compound stability, a targeted library of candidate molecules designed on the structural basis of the first lead has been synthesized and tested against MV. We have identified an improved lead with low toxicity and high stability (half-life ≫ 16 h) that prevents viral entry and hence infection. This compound shows high MV specificity and strong activity (50% inhibitory concentration = 0.6 to 3.0 μM, depending on the MV genotype) against a panel of wild-type MV strains representative of viruses that are currently endemic in the field.
Intensive Therapy with Ceftobiprole Medocaril of Experimental Foreign-Body Infection by Methicillin-Resistant
Staphylococcus aureus
Authors: Vaudaux Pierre , Gjinovci Asllan , Bento Manuela , Li Dongmei , Schrenzel Jacques , Lew Daniel P. 
Published: August 2005

ABSTRACT

The therapeutic activity of ceftobiprole medocaril, the water-soluble prodrug of ceftobiprole, was compared to that of vancomycin in a rat tissue cage model of chronic methicillin-resistant
Staphylococcus aureus
(MRSA) foreign-body infection. The MICs and MBCs of ceftobiprole and vancomycin in Mueller-Hinton broth for strain MRGR3 were 1 and 4 and 1 and 2 μg/ml, respectively. In vitro elimination rates of strain MRGR3 of 4 and 8 μg/ml of ceftobiprole or vancomycin were equivalent. After 2 weeks of infection, mean ± standard error of the mean viable counts of strain MRGR3 were 6.83 ± 0.11 log CFU/ml of tissue cage fluid (
n
= 87). High-dose regimens of ceftobiprole medocaril (equivalent to 150 mg/kg of ceftobiprole) or 50 mg/kg vancomycin produced nearly identical average peak and trough levels of ceftobiprole and vancomycin in tissue cage fluid, which exceeded the MBC of either antibiotic towards strain MRGR3 for ≥75% of each dosing interval. After 7 days of therapy with ceftobiprole medocaril or vancomycin, average counts of MRGR3 decreased significantly (
P
< 0.02) by 0.68 ± 0.28 (
n
= 29) and 0.88 ± 0.22 (
n
= 28) log CFU/ml of tissue cage fluid, respectively, compared with cages of untreated animals, but were not significantly different from each other. No resistant mutants were detected on ceftobiprole-supplemented agar following therapy with this cephalosporin. The in vivo activity of ceftobiprole medocaril against chronic MRSA foreign-body infections was equivalent to that of vancomycin and did not lead to the emergence of resistant subpopulations.
Atazanavir Signature I50L Resistance Substitution Accounts for Unique Phenotype of Increased Susceptibility to Other Protease Inhibitors in a Variety of Human Immunodeficiency Virus Type 1 Genetic Backbones
Authors: Weinheimer S. , Discotto L. , Friborg J. , Yang H. , Colonno R. 
Published: August 2005

ABSTRACTSubstitution of leucine for isoleucine at residue 50 (I50L) of human immunodeficiency virus (HIV) protease is the signature substitution for atazanavir (ATV) resistance. A unique phenotypic profile has been associated with viruses containing the I50L substitution, which produces ATV-specific resistance and increased susceptibility to most other approved HIV protease inhibitors (PIs). The basis for this unique phenotype has not been clearly elucidated. In this report, a direct effect of I50L on the susceptibility to the PI class is described. Cell-based protease assays using wild-type and PI-resistant proteases from laboratory and clinical isolates and in vitro antiviral assays were used to demonstrate a strong concordance between changes in PI susceptibility at the level of protease inhibition and changes in susceptibility observed at the level of virus infection. The results show that the induction of ATV resistance and increased susceptibility to other PIs by the I50L substitution is likely determined at the level of protease inhibition. Moreover, the I50L substitution functions to increase PI susceptibility even in the presence of other primary and secondary PI resistance substitutions. These findings may have implications regarding the optimal sequencing of PI therapies necessary to preserve PI treatment options of patients with ATV-resistant HIV infections.
In Vitro and In Vivo Effects of Soluble, Monovalent Globotriose on Bacterial Attachment and Colonization
Authors: Leach James L. , Garber Stacey A. , Marcon Andrea A. , Prieto Pedro A. 
Published: August 2005

ABSTRACT

Epithelial cells lining the urinary tract are rich in globo series glycolipids, structurally defined by a Galα1,4Gal motif in the oligosaccharide moiety of this glycolipid family. This Galα1,4Gal motif is the attachment target for the P-fimbrial adhesin of uropathogenic
Escherichia coli
. We investigated the ability of a trisaccharide analog of this core motif, globotriose (Galα1,4Galβ1,4Glc), to interfere with uropathogen attachment and colonization in vitro and in vivo. We assessed the ability of globotriose to inhibit and reverse the binding and agglutination of a P-fimbriated strain of
E. coli
(JR1) using human erythrocytes and immortalized human colonic epithelial cells as targets. Globotriose (5 mg/ml) completely inhibited and reversed cell agglutination and caused a 10- to 100-fold reduction in JR1 binding to target cells, as determined by flow cytometry. In preparation for an in vivo efficacy study, we investigated the distribution and pharmacokinetics of globotriose in the BALB/c mouse. Globotriose was administered via the tail vein, targeting an instantaneous plasma concentration of 5 mg/ml, and in a different experiment, animals were gavaged at 10 times the intravenous (i.v.) dose. Globotriose was rapidly cleared from plasma (half-life [
t
1/2
], 6 min) and slowly excreted via the kidney (
t
1/2
, 4 h). Urine levels of >5 mg/ml were maintained from 4 to 12 h after the i.v. bolus dose, which resulted in a 1-log reduction in established bladder colonization by JR1. These results suggest that free, soluble globotriose is a feasible alternative therapy for urinary tract infections.
Molecular Basis of Azithromycin-Resistant
Pseudomonas aeruginosa
Biofilms
Authors: Gillis Richard J. , White Kimberly G. , Choi Kyoung-Hee , Wagner Victoria E. , Schweizer Herbert P. , Iglewski Barbara H. 
Published: August 2005

ABSTRACT

Pseudomonas aeruginosa
biofilms are extremely recalcitrant to antibiotic treatment. Treatment of cystic fibrosis patients with azithromycin (AZM) has shown promise. We used DNA microarrays to identify differentially expressed transcripts in developing
P. aeruginosa
biofilms exposed to 2 μg/ml AZM. We report that transcripts for multiple restriction-nodulation-cell division (RND) efflux pumps, known to be involved in planktonic antibiotic resistance, and transcripts involved in type III secretion were upregulated in the resistant biofilms that developed in the presence of AZM. Interestingly, the MexAB-OprM and MexCD-OprJ efflux pumps, but not type III secretion, appear to be integral to biofilm formation in the presence of AZM, as evidenced by the fact that a mutant deleted in both
mexAB-oprM
and
mexCD-oprJ
was unable to form a biofilm in the presence of AZM. A mutant deleted in type III secretion was still able to form biofilms in the presence of drug. Furthermore, single
mexAB-oprM
- and
mexCD-oprJ
-null mutants were able to form a biofilm in the presence of drug, indicating that either of the pumps can confer resistance to AZM during biofilm development. In contrast to planktonically grown cells, where no
mexC
expression was detectable regardless of the presence of AZM, biofilms exhibited induction of
mexC
expression from the outset of their formation, but only in the presence of AZM.
mexA
, which is constitutively expressed in planktonic cells, was uniformly expressed in biofilms regardless of the presence of AZM. These data indicate that the MexCD-OprJ pump acts as a biofilm-specific mechanism for AZM resistance.