bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and Short-Term Safety of 873140, a Novel CCR5 Antagonist, in Healthy Adult Subjects
Authors: Adkison Kimberly K. , Shachoy-Clark Anne , Fang Lei , Lou Yu , O'Mara Kathy , Berrey M. Michelle , Piscitelli Stephen C. 
Published: June 2005

ABSTRACT

873140 is a novel CCR5 antagonist with potent in vitro anti-human immunodeficiency virus (HIV) activity. This study was a double-blind, randomized, placebo-controlled, single- and repeat-dose escalation investigation of the safety, pharmacokinetics, and food effect of 873140 in 70 adult subjects. During single-dose escalation, three cohorts (each composed of 10 subjects, with 8 subjects receiving the active drug and 2 subjects receiving the placebo [8 active and 2 placebo]) received doses of 50, 200, 400, 800, and 1,200 mg after an overnight fast, or 400 mg plus a standard high-fat breakfast in an alternating panel design. During repeat-dose escalation, four cohorts (each with 8 active and 2 placebo) received doses of 200, 400, 600, or 800 mg every 12 h (BID) for 8 days. Laboratory safety tests, vital signs, and electrocardiograms (ECGs) were performed at regular intervals, and blood samples were obtained for pharmacokinetics. Single and repeat doses of 50 mg to 800 mg were well tolerated, with no serious adverse events and no grade 3 or 4 adverse events. The mild-to-moderate side effects were primarily gastrointestinal and included abdominal cramping, nausea, and diarrhea. No specific trends in laboratory parameters or clinically significant ECG changes were noted. Plasma 873140 concentrations increased rapidly; the median time to maximum concentration of drug in serum was 1.75 to 5 h. The median area under the plasma concentration-time profile (AUC) and the maximum concentration of drug in serum (
C
max
) ranged from 127 ng · h/ml and 24 ng/ml at 200 mg BID to 329 ng · h/ml and 100 ng/ml at 800 mg BID, respectively. Food consumption increased the AUC and
C
max
by a mean of 1.7- and 2.2-fold, respectively. The pharmacokinetic and safety profile supports the continued investigation of 873140 with HIV-infected subjects.
Sixteen Homologs of the Mex-Type Multidrug Resistance Efflux Pump in
Bacteroides fragilis
Authors: Ueda Ohmi , Wexler Hannah M. , Hirai Kaname , Shibata Yukinaga , Yoshimura Fuminobu , Fujimura Setsuo 
Published: June 2005

ABSTRACT

Sixteen homologs of multidrug resistance efflux pump operons of the resistance-nodulation-cell division (RND) family were found in the
Bacteroides fragilis
genome sequence by homology searches. Disruption mutants were made to the
mexB
homologs of the four genes most similar to
Pseudomonas aeruginosa mexB
. Reverse transcription-PCR was conducted and indicated that the genes were transcribed in a polycistronic fashion and that the promoter was upstream of
bmeA
(the
mexA
homolog). One of these disruption mutants (in
bmeB
, the
mexB
homolog) was more susceptible than the parental strain to certain cephems, polypeptide antibiotics, fusidic acid, novobiocin, and puromycin. The gene for this homolog and the adjacent upstream gene,
bmeA
, were cloned in a hypersensitive
Escherichia coli
host. The resultant transformants carrying
B. fragilis bmeAB
were more resistant to certain agents; these agents also had lower MICs for the
B. fragilis bmeB
disruption mutants than for the parental strain. The putative efflux pump operon is composed of
bmeA
,
bmeB
, and
bmeC
(a putative outer membrane channel protein homologous with OprM). Addition of the efflux pump inhibitors, carbonyl cyanide
m
-chlorophenylhydrazone (a proton conductor that eliminates the energy source) and Phe-Arg β-naphthylamide (MC-207,110) (the first specific inhibitor described for RND pumps in
P. aeruginosa
), resulted in lowered MICs in the parental strain but not in the
bmeB
disruption mutant, indicating that the
bmeB
pump is affected by these inhibitors. This is the first description of RND type pumps in the genus
Bacteroides
.
Imipenem for Treatment of Tuberculosis in Mice and Humans
Authors: Chambers Henry F. , Turner Joan , Schecter Gisela F. , Kawamura Masae , Hopewell Philip C. 
Published: June 2005

ABSTRACT

Chemotherapy of tuberculosis caused by multiple-drug-resistant (MDR) strains is problematic because of choices limited to relatively inefficacious and toxic drugs. Some beta-lactam antibiotics are active against
Mycobacterium tuberculosis
in vitro. We investigated the efficacy of imipenem in a mouse model of tuberculosis and in humans with MDR tuberculosis. Mice infected with
M. tuberculosis
strain H37Rv were treated with isoniazid or imipenem. Residual organisms in lung and spleen and survival of imipenem-treated mice were compared to those of untreated or isoniazid-treated mice. Ten patients with MDR tuberculosis also were treated with imipenem in combination with other first- or second-line agents; elimination of
M. tuberculosis
from sputum samples was measured by quantitative culture. Although it was less effective than isoniazid, imipenem significantly reduced the numbers of
M. tuberculosis
organisms in lungs and spleens and improved survival of mice. Eight of 10 patients with numerous risk factors for poor outcomes responded to imipenem combination therapy with conversion of cultures to negative. Seven remained culture-negative off of therapy. There were two deaths, one of which was due to active tuberculosis. Organisms were eliminated from the sputa of responders at a rate of 0.35 log
10
CFU/ml/week. Relapse upon withdrawal of imipenem and development of resistance to imipenem in a nonresponder suggest that imipenem exerts antimycobacterial activity in humans infected with
M. tuberculosis
. Imipenem had antimycobacterial activity both in a mouse model and in humans at high risk for failure of treatment for MDR tuberculosis.
Helicobacter pylori
Accumulates Photoactive Porphyrins and Is Killed by Visible Light
Authors: Hamblin Michael R. , Viveiros Jennifer , Yang Changming , Ahmadi Atosa , Ganz Robert A. , Tolkoff M. Joshua 
Published: June 2005

ABSTRACT

Helicobacter pylori
colonizes the mucus layer of the human stomach and duodenum, causes chronic gastritis, gastric ulcer, and is a risk factor for gastric adenocarcinoma. There is a 20% failure rate in antibiotic therapy, which is increasingly due to antibiotic resistance and necessitates the search for alternative antimicrobial methods. We have discovered that
H. pylori
when cultured in liquid medium, accumulates significant quantities of coproporphyrin and protoporphyrin IX, both in the cells and secreted into the medium. These photoactive porphyrins lead to cell death (up to 5 logs) by photodynamic action upon illumination with low doses of visible light, with blue/violet light being most efficient. The degree of killing increases with the age of the culture and is greater than that found with
Propionibacterium acnes
(another bacterium known to be photosensitive due to porphyrin accumulation). Both virulent and drug-resistant strains are killed. The data suggest that phototherapy might be used to treat
H. pylori
infection in the human stomach.
Safety, Pharmacokinetics, and Efficacy of (+/−)-β-2′,3′-Dideoxy-5-Fluoro-3′-Thiacytidine with Efavirenz and Stavudine in Antiretroviral-Naïve Human Immunodeficiency Virus-Infected Patients
Authors: Herzmann C. , Arastèh K. , Murphy R. L. , Schulbin H. , Kreckel P. , Drauz D. , Schinazi R. F. , Beard A. , Cartee L. , Otto M. J. 
Published: June 2005

ABSTRACT

Racivir [RCV; (+/−)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine], a 50:50 racemic mixture of the two β nucleoside enantiomers, is currently in development for the treatment of human immunodeficiency virus type 1 (HIV-1) infections. RCV was administered once a day orally for 14 days at doses of 200, 400, or 600 mg in combination with stavudine and efavirenz to HIV-1-infected treatment-naïve male volunteers in a phase Ib/IIa study. Six volunteers at each dose were monitored for a total of 35 days for tolerance, pharmacokinetics, and plasma HIV RNA levels. RCV in combination with stavudine and efavirenz was well tolerated at all doses tested. Pharmacokinetic parameters were dose proportional, and the maximum concentration of drug in serum at all doses exceeded the 90% effective concentration for wild-type HIV-1. Viral loads dropped as expected in all dosage groups, with mean reductions from 1.13 to 1.42 log
10
by day 4 and 2.02 to 2.43 log
10
by day 14. HIV RNA levels remained suppressed for more than 2 weeks in the absence of any additional therapy, with mean viral loads ranging from 2.1 to 2.6 log
10
below baseline through day 28. By day 35, HIV RNA levels began to increase but still remained >1 log
10
below baseline levels.
Genetic Approach To Study the Relationship between Penicillin-Binding Protein 3 Mutations and
Haemophilus influenzae
β-Lactam Resistance by Using Site-Directed Mutagenesis and Gene Recombinants
Authors: Osaki Yumi , Sanbongi Yumiko , Ishikawa Midori , Kataoka Hiroshi , Suzuki Takahisa , Maeda Kumiko , Ida Takashi 
Published: June 2005

ABSTRACT

To clarify the relationship between mutations commonly found for penicillin-binding protein 3 (PBP 3) of β-lactamase-nonproducing ampicillin-resistant (BLNAR)
Haemophilus influenzae
isolates and β-lactam resistance, single and multiple amino acid mutations at positions 377, 385, 389, 517, and 526 were introduced into PBP 3 of a β-lactam-susceptible Rd strain by site-directed mutagenesis. Twelve isogenic recombinant strains were challenged with nine β-lactam antibiotics. Replacement of the asparagine at position 526 with lysine (N526K) increased the resistance to imipenem eightfold and increased the resistance to various cephalosporins two- to eightfold. Substitution of threonine for serine at position 385 (S385T) and/or substitution of phenylalanine for leucine at position 389 (L389F), in addition to the N526K mutation, led to two- to fourfold additional increases in cephalosporin resistance. An isoleucine-to-methionine substitution at position 377 did not change the antibiotic sensitivity of any of the recombinant strains also carrying other PBP 3 mutations tested. Thirty-six clinical isolates carrying a PBP 3 gene (
ftsI
) with the S385T, L389F, R517H, and/or N526K mutation were chosen from among 279 clinical isolates collected in Japan, and the isolates were grouped into six classes on the basis of the patterns of the four mutations in PBP 3. Rd recombinants were made with each of the
ftsI
genes. The levels of resistance to β-lactams varied between recombinants of different classes but were comparable for those of the same class. The levels of resistance to cephalosporins of these recombinants were similar to those of the parent clinical isolates, while those to ampicillin and carbapenems were lower. These results indicate that resistance to β-lactams, at least to cephalosporins, depends in large part on the PBP 3 mutations R517H, N526K, S385T, and L389F.
Amino Acid Substitution inTrichophyton rubrumSqualene Epoxidase Associated with Resistance to Terbinafine
Authors: Osborne Colin S. , Leitner Ingrid , Favre Bertrand , Ryder Neil S. 
Published: June 2005

ABSTRACTThere has only been one clinically confirmed case of terbinafine resistance in dermatophytes, where six sequentialTrichophyton rubrumisolates from the same patient were found to be resistant to terbinafine and cross-resistant to other squalene epoxidase (SE) inhibitors. Microsomal SE activity from these resistant isolates was insensitive to terbinafine, suggesting a target-based mechanism of resistance (B. Favre, M. Ghannoum, and N. S. Ryder, Med. Mycol. 42:525-529, 2004). In this study, we have characterized at the molecular level the cause of the resistant phenotype of these clinical isolates. Cloning and sequencing of the SE gene and cDNA fromT. rubrumrevealed the presence of an intron in the gene and an open reading frame encoding a protein of 489 residues, with an equivalent similarity (57%) to both yeast and mammalian SEs. The nucleotide sequences of SE from two terbinafine-susceptible strains were identical whereas those of terbinafine-resistant strains, serially isolated from the same patient, each contained the same single missense introducing the amino acid substitution L393F. Introduction of the corresponding substitution in theCandida albicansSE gene (L398F) and expression of this gene inSaccharomyces cerevisiaeconferred a resistant phenotype to the transformants when compared to those expressing the wild-type sequence. Terbinafine resistance in theseT. rubrumclinical isolates appears to be due to a single amino acid substitution in SE.
Antimicrobial and Chemoattractant Activity, Lipopolysaccharide Neutralization, Cytotoxicity, and Inhibition by Serum of Analogs of Human Cathelicidin LL-37
Authors: Ciornei Cristina D. , Sigurdardóttir Thorgerdur , Schmidtchen Artur , Bodelsson Mikael 
Published: June 2005

ABSTRACTAntimicrobial peptides have been evaluated in vitro and in vivo as alternatives to conventional antibiotics. Apart from being antimicrobial, the native human cathelicidin-derived peptide LL-37 (amino acids [aa] 104 to 140 of the human cathelicidin antimicrobial peptide) also binds and neutralizes bacterial lipopolysaccharide (LPS) and might therefore have beneficial effects in the treatment of septic shock. However, clinical trials have been hampered by indications of toxic effects of LL-37 on mammalian cells and evidence that its antimicrobial effects are inhibited by serum. For the present study, LL-37 was compared to two less hydrophobic fragments obtained by N-terminal truncation, named 106 (aa 106 to 140) and 110 (aa 110 to 140), and to a previously described more hydrophobic variant, the 18-mer LLKKK, concerning antimicrobial properties, lipopolysaccharide neutralization, toxicity against human erythrocytes and cultured vascular smooth muscle cells, chemotactic activity, and inhibition by serum. LL-37, fragments 106 and 110, and the 18-mer LLKKK inhibited the growth ofEscherichia coli,Pseudomonas aeruginosa,Staphylococcus aureus, andCandida albicansin a radial diffusion assay, inhibited lipopolysaccharide-induced vascular nitric oxide production, and attracted neutrophil granulocytes similarly. While fragments 106 and 110 caused less hemolysis and DNA fragmentation in cultured cells than did LL-37, the 18-mer LLKKK induced severe hemolysis. The antibacterial effect of fragments 106 and 110 was not affected by serum, while the effect of LL-37 was reduced. We concluded that the removal of N-terminal hydrophobic amino acids from LL-37 decreases its cytotoxicity as well as its inhibition by serum without negatively affecting its antimicrobial or LPS-neutralizing action. Such LL-37-derived peptides may thus be beneficial for the treatment of patients with sepsis.
Cryptococcus neoformans
Resistance to Echinocandins: (1,3)β-Glucan Synthase Activity Is Sensitive to Echinocandins
Authors: Maligie Marybeth A. , Selitrennikoff Claude P. 
Published: June 2005

ABSTRACT

(1,3)β-
d
-Glucan synthase (EC 2.4.1.34. UDP-glucose: 1,3-β-
d
-glucan 3-β-glucosyltransferase) uses UDP-glucose as substrate and catalyzes the polymerization of glucose ([1,3]-β-linkages) to form the major carbohydrate component of the fungal cell wall. We have optimized in vitro assay conditions for (1,3)β-glucan synthase activity from
Cryptococcus neoformans
. Cells lysed in 50 mM Tris, pH 7.75, containing 20% glycerol, 2 mM NaF, 1 mM dithiothreitol, 0.1 mM phenylmethylsulfonyl fluoride, 5 mM MgCl
2
, 0.1% protease and phosphatase inhibitor cocktails, and 60 μM GTPγS produced maximum specific activity in vitro. We tested in vitro
C. neoformans
(1,3)β-glucan synthase activity against the (1,3)β-glucan synthase inhibitors, caspofungin and cilofungin, and have determined that (1,3)β-glucan synthase activity is very sensitive (apparent

K
i

of 0.17 ± 0.02 μM and 22 ± 5.7 μM, respectively) to these echinocandins. Taken together with high MICs for
C. neoformans
(caspofungin MIC, 16 μg/ml; cilofungin MIC, 64 μg/ml), our results indicate that
C. neoformans
is resistant to caspofungin and cilofungin by a mechanism(s) unrelated to (1,3)β-glucan synthase resistance.
3-Aminooxy-1-Aminopropane and Derivatives Have an Antiproliferative Effect on Cultured
Plasmodium falciparum
by Decreasing Intracellular Polyamine Concentrations
Authors: Das Gupta Robin , Krause-Ihle Tanja , Bergmann Bärbel , Müller Ingrid B. , Khomutov Alex R. , Müller Sylke , Walter Rolf D. , Lüersen Kai 
Published: June 2005

ABSTRACT

The intraerythrocytic development of
Plasmodium falciparum
correlates with increasing levels of the polyamines putrescine, spermidine, and spermine in the infected red blood cells; and compartmental analyses revealed that the majority is associated with the parasite. Since depletion of cellular polyamines is a promising strategy for inhibition of parasite proliferation, new inhibitors of polyamine biosynthesis were tested for their antimalarial activities. The ornithine decarboxylase (ODC) inhibitor 3-aminooxy-1-aminopropane (APA) and its derivatives CGP 52622A and CGP 54169A as well as the
S
-adenosylmethionine decarboxlyase (AdoMetDC) inhibitors CGP 40215A and CGP 48664A potently affected the bifunctional
P. falciparum
ODC-AdoMetDC, with

K
i

values in the low nanomolar and low micromolar ranges, respectively. Furthermore, the agents were examined for their in vitro plasmodicidal activities in 48-h incubation assays. APA, CGP 52622A, CGP 54169A, and CGP 40215A were the most effective, with 50% inhibitory concentrations below 3 μM. While the effects of the ODC inhibitors were completely abolished by the addition of putrescine, growth inhibition by the AdoMetDC inhibitor CGP 40215A could not be antagonized by putrescine or spermidine. Moreover, CGP 40215A did not affect the cellular polyamine levels, indicating a mechanism of action against
P. falciparum
independent of polyamine synthesis. In contrast, the ODC inhibitors led to decreased cellular putrescine and spermidine levels in
P. falciparum
, supporting the fact that they exert their antimalarial activities by inhibition of the bifunctional ODC-AdoMetDC.
Frequency of Spontaneous Mutations That Confer Antibiotic Resistance in
Chlamydia
spp
Authors: Binet Rachel , Maurelli Anthony T. 
Published: June 2005

ABSTRACT

Mutations in rRNA genes (
rrn
) that confer resistance to ribosomal inhibitors are typically recessive or weakly codominant and have been mostly reported for clinical strains of pathogens possessing only one or two
rrn
operons, such as
Helicobacter pylori
and
Mycobacterium
spp. An analysis of the genome sequences of several members of the
Chlamydiaceae
revealed that these obligate intracellular bacteria harbor only one or two sets of rRNA genes. To study the contribution of rRNA mutations to the emergence of drug resistance in the
Chlamydiaceae
, we used the sensitivities of
Chlamydia trachomatis
L2 (two
rrn
operons) and
Chlamydophila psittaci
6BC (one
rrn
operon) to the aminoglycoside spectinomycin as a model. Confluent cell monolayers were infected in a plaque assay with about 10
8
wild-type infectious particles and then treated with the antibiotic. After a 2-week incubation time, plaques formed by spontaneous spectinomycin-resistant (Spc
r
) mutants appeared with a frequency of 5 × 10
−5
for
C. psittaci
6BC. No Spc
r
mutants were isolated for
C. trachomatis
L2, although the frequencies of rifampin resistance were in the same range for both strains (i.e., 10
−7
). The risk of emergence of
Chlamydia
strains resistant to tetracyclines and macrolides, the ribosomal drugs currently used to treat chlamydial infections, is discussed.
Human Volunteers Receiving
Escherichia coli
Phage T4 Orally: a Safety Test of Phage Therapy
Authors: Bruttin Anne , Brüssow Harald 
Published: June 2005

ABSTRACT

Fifteen healthy adult volunteers received in their drinking water a lower
Escherichia coli
phage T4 dose (10
3
PFU/ml), a higher phage dose (10
5
PFU/ml), and placebo. Fecal coliphage was detected in a dose-dependent way in volunteers orally exposed to phage. All volunteers receiving the higher phage dose showed fecal phage 1 day after exposure; this prevalence was only 50% in subjects receiving the lower phage dose. No fecal phage was detectable a week after a 2-day course of oral phage application. Oral phage application did not cause a decrease in total fecal
E. coli
counts. In addition, no substantial phage T4 replication on the commensal
E. coli
population was observed. No adverse events related to phage application were reported. Serum transaminase levels remained in the normal range, and neither T4 phage nor T4-specific antibodies were observed in the serum of the subjects at the end of the study. This is, to our knowledge, the first safety test in the recent English literature which has measured the bioavailability of oral phage in humans and is thus a first step to the rational evaluation of phage therapy for diarrheal diseases.
Colonization and Resistance Dynamics of Gram-Negative Bacteria in Patients during and after Hospitalization
Authors: Filius P. Margreet G. , Gyssens Inge C. , Kershof Irma M. , Roovers Patty J. E. , Ott Alewijn , Vulto Arnold G. , Verbrugh Henri A. , Endtz Hubert P. 
Published: June 2005

ABSTRACT

The colonization and resistance dynamics of aerobic gram-negative bacteria in the intestinal and oropharyngeal microfloras of patients admitted to intensive care units (ICU) and general wards were investigated during and after hospitalization. A total of 3,316 specimens were obtained from patients upon admission, once weekly during hospitalization, at discharge from the ICU, at discharge from the hospital, and 1 and 3 months after discharge from the hospital. Five colonies per specimen were selected for identification and susceptibility testing. In both patient populations, the gram-negative colonization rates in oropharyngeal specimens increased during hospitalization and did not decrease in the 3 months after discharge. In rectal specimens, colonization rates decreased during hospitalization and increased after discharge. There was a change in species distribution among the dominant microfloras during hospitalization.
Klebsiella
spp.,
Enterobacter
spp.,
Serratia marcescens
, and
Pseudomonas aeruginosa
were isolated more often, whereas the frequency of
Escherichia coli
declined. The percentage of ICU patients colonized with ampicillin- and/or cephalothin-resistant fecal
E. coli
was significantly increased at discharge from the hospital and did not change in the 3 months after discharge. The emergence of multidrug resistance was observed for
E. coli
during patient stays in the ICU. Resistance frequencies in
E. coli
significantly increased with the length of stay in the ICU. For the general ward population, no significant changes in resistance frequencies were found during hospitalization. From a population perspective, the risk of dissemination of resistant gram-negative bacteria into the community through hospitalized patients appears to be low for general ward patients but is noticeably higher among ICU patients.