bluuebunny/crossref_metadata_2025_split huggingface dataset:
Double-Blind Evaluation of the Safety and Pharmacokinetics of Multiple Oral Once-Daily 750-Milligram and 1-Gram Doses of Levofloxacin in Healthy Volunteers
Authors: Chien Shu-Chean , Wong Frank A. , Fowler Cynthia L. , Callery-D’Amico Susan V. , Williams R. Rex , Nayak Ramchandra , Chow Andrew T. 
Published: October 2018

ABSTRACT

The safety and pharmacokinetics of once-daily oral levofloxacin in 16 healthy male volunteers were investigated in a randomized, double-blind, placebo-controlled study. Subjects were randomly assigned to the treatment (
n
= 10) or placebo group (
n
= 6). In study period 1, 750 mg of levofloxacin or a placebo was administered orally as a single dose on day 1, followed by a washout period on days 2 and 3; dosing resumed for days 4 to 10. Following a 3-day washout period, 1 g of levofloxacin or a placebo was administered in a similar fashion in period 2. Plasma and urine levofloxacin concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by model-independent methods. Levofloxacin was rapidly absorbed after single and multiple once-daily 750-mg and 1-g doses with an apparently large volume of distribution. Peak plasma levofloxacin concentration (
C
max
) values were generally attained within 2 h postdose. The mean values of
C
max
and area under the concentration-time curve from 0 to 24 h (AUC
0–24
) following a single 750-mg dose were 7.1 μg/ml and 71.3 μg · h/ml, respectively, compared to 8.6 μg/ml and 90.7 μg · h/ml, respectively, at steady state. Following the single 1-g dose, mean
C
max
and AUC
0–24
values were 8.9 μg/ml and 95.4 μg · h/ml, respectively; corresponding values at steady state were 11.8 μg/ml and 118 μg · h/ml. These
C
max
and AUC
0–24
values indicate modest and similar degrees of accumulation upon multiple dosing at the two dose levels. Values of apparent total body clearance (CL/
F
), apparent volume of distribution (
V
ss
/
F
), half-life (
t
1/2
), and renal clearance (CL
R
) were similar for the two dose levels and did not vary from single to multiple dosing. Mean steady-state values for CL/
F
,
V
ss
/
F
,
t
1/2
, and CL
R
following 750 mg of levofloxacin were 143 ml/min, 100 liters, 8.8 h, and 116 ml/min, respectively; corresponding values for the 1-g dose were 146 ml/min, 105 liters, 8.9 h, and 105 ml/min. In general, the pharmacokinetics of levofloxacin in healthy subjects following 750-mg and 1-g single and multiple once-daily oral doses appear to be consistent with those found in previous studies of healthy volunteers given 500-mg doses. Levofloxacin was well tolerated at either high dose level. The most frequently reported drug-related adverse events were nausea and headache.
Dual Inhibition of Human Rhinovirus 2A and 3C Proteases by Homophthalimides
Authors: Wang Q. May , Johnson Robert B. , Jungheim Louis N. , Cohen Jeffrey D. , Villarreal Elcira C. 
Published: October 2018

ABSTRACT
The 2A and 3C proteases encoded by human rhinoviruses (HRVs) are attractive targets for antiviral drug development due to their important roles in viral replication. Homophthalimides were originally identified as inhibitors of rhinovirus 3C protease through our screening effort. Previous studies have indicated that the antiviral activity of certain homophthalimides exceeded their in vitro inhibitory activity against the viral 3C protease, suggesting that an additional mechanism might be involved. Reported here is the identification of homophthalimides as potent inhibitors for another rhinovirus protease, designated 2A. Several homophthalimides exhibit time-dependent inhibition of the 2A protease in the low-micromolar range, and enzyme-inhibitor complexes were identified by mass spectrometry. Compound LY343814, one of the most potent inhibitors against HRV14 2A protease, had an antiviral 50% inhibitory concentration of 4.2 μM in the cell-based assay. Our data reveal that homophthalimides are not only 3C but also 2A protease inhibitors in vitro, implying that the antiviral activity associated with these compounds might result from inactivation of both 2A and 3C proteases in vivo. Since the processing of the viral polyprotein is hierarchical, dual inhibition of the two enzymes may result in cooperative inhibition of viral replication. On the basis of the current understanding of their enzyme inhibitory mechanism, homophthalimides, as a group of novel nonpeptidic antirhinovirus agents, merit further structure-action relationship studies.
Efficacy of Sulfamethoxypyridazine in a Murine Model of
Pneumocystis carinii
Pneumonia
Authors: Bartlett Marilyn S. , Shaw Margaret M. , Smith James W. , Meshnick Steven R. 
Published: October 2018

ABSTRACT

Sulfamethoxazole is the component of co-trimoxazole responsible for its efficacy against
Pneumocystis carinii
pneumonia, but this drug is associated with frequent adverse effects. Sulfamethoxypyridazine is significantly more effective than sulfamethoxazole against a murine model of
P. carinii
and might be a candidate for testing in infected patients.
Mutations in
aarE
, the
ubiA
Homolog of
Providencia stuartii
, Result in High-Level Aminoglycoside Resistance and Reduced Expression of the Chromosomal Aminoglycoside 2′-
N
-Acetyltransferase
Authors: Paradise Michael R. , Cook Gregory , Poole Robert K. , Rather Philip N. 
Published: October 2018

ABSTRACT

The
aarE1
allele was identified on the basis of the resulting phenotype of increased aminoglycoside resistance. The
aarE1
mutation also resulted in a small-colony phenotype and decreased levels of
aac(2′)-Ia
mRNA. The deduced AarE gene product displayed 61% amino acid identity to the
Escherichia coli
UbiA protein, an octaprenyltransferase required for the second step of ubiquinone biosynthesis. Complementation experiments in both
Providencia stuartii
and
E. coli
demonstrated that
aarE
and
ubiA
are functionally equivalent.
In Vitro Susceptibilities of
Bordetella pertussis
and
Bordetella parapertussis
to Two Ketolides (HMR 3004 and HMR 3647), Four Macrolides (Azithromycin, Clarithromycin, Erythromycin A, and Roxithromycin), and Two Ansamycins (Rifampin and Rifapentine)
Authors: Hoppe Jörg E. , Bryskier André 
Published: October 2018

ABSTRACT

When tested by agar dilution on Mueller-Hinton agar supplemented with 5% horse blood, the ketolides HMR 3004 and HMR 3647 were slightly more active (MIC at which 90% of the isolates were inhibited [MIC
90
], 0.03 μg/ml) against
Bordetella pertussis
than azithromycin, clarithromycin, erythromycin A, and roxithromycin. Azithromycin (MIC
90
, 0.06 μg/ml) was the most active compound against
B. parapertussis
. Rifampin and rifapentine were considerably less active.
Human Cytomegalovirus Mutant with Sequence-Dependent Resistance to the Phosphorothioate Oligonucleotide Fomivirsen (ISIS 2922)
Authors: Mulamba Gilbert B. , Hu André , Azad Raana F. , Anderson Kevin P. , Coen Donald M. 
Published: October 2018

ABSTRACT
A human cytomegalovirus mutant that was isolated for resistance (10-fold) to the antisense oligonucleotide fomivirsen (ISIS 2922) exhibited cross-resistance to a modified derivative of fomivirsen with an identical base sequence but little or no resistance to an oligonucleotide with an unrelated sequence. No changes in the mutant’s DNA corresponding to the fomivirsen target sequence were found.
Field Evaluation of the Prophylactic Effect of an Isometamidium Sustained-Release Device against Trypanosomiasis in Cattle
Authors: Diarra B. , Diall O. , Geerts S. , Kageruka P. , Lemmouchi Y. , Schacht E. , Eisler M. C. , Holmes P. 
Published: October 2018

ABSTRACTIn order to compare the prophylactic effect provided by a poly(d,l-lactide) sustained-release device (SRD) containing isometamidium (ISMM) with that provided by the classical intramuscular injection of the drug, a field trial was carried out at the Madina Diassa Ranch in Mali. One- to 3-year-old N’Dama cattle were randomly divided into three groups. The first group (n= 42) was treated with ISMM at a dose of 1 mg/kg of body weight, the second group (n= 44) received the same dose of the drug via an SRD, which was subcutaneously implanted in the shoulder region, and the third group (n= 36) was kept as an untreated control group. All animals were treated with diminazene aceturate (7 mg/kg of body weight) 2 weeks before the start of the experiment and were tested monthly by the buffy coat technique for a period of 8 months.Glossina morsitans submorsitanswas the most important tsetse species, with apparent densities (number of catches/trap/day) varying between 11.9 and 38.7 over the experimental period. Eight months after treatment the cumulative infection rates were 27.7, 58.5, and 77.4% in the group with the SRD implant, the group receiving the intramuscular injection, and the control group, respectively. Statistical analysis showed that the incidence of trypanosomiasis was significantly lower (P= 0.006) in the group which received ISMM via the SRD than in the one which was treated with ISMM intramuscularly.
Biological Characterization of Endotoxins Released from Antibiotic-TreatedPseudomonas aeruginosaandEscherichia coli
Authors: Kirikae Teruo , Kirikae Fumiko , Saito Shinji , Tominaga Kaoru , Tamura Hirohi , Uemura Yayoi , Yokochi Takashi , Nakano Masayasu 
Published: October 2018

ABSTRACTThe supernatants taken fromPseudomonas aeruginosaandEscherichia colicultures in human sera or chemically defined M9 medium in the presence of ceftazidime (CAZ) contained high levels of endotoxin, while those taken from the same cultures in the presence of imipenem (IPM) yielded a very low level of endotoxin. The biological activities of endotoxin in the supernatants were compared with those of phenol water-extracted lipopolysaccharide (LPS). The endotoxin released from the organisms as a result of CAZ treatment (CAZ-released endotoxin) contained a large amount of protein. The protein, however, lacked endotoxic activity, since the endotoxin did not show any in vivo toxic effects in LPS-hyporesponsive C3H/HeJ mice sensitized withd-(+)-galactosamine (GalN) or any activation of C3H/HeJ mouse macrophages in vitro. The activities of CAZ- and IPM-released endotoxin (as assessed by a chromogenicLimulustest) were fundamentally the same as those ofP. aeruginosaLPS, since their regression lines were parallel. The CAZ-released endotoxin was similar to purified LPS with respect to the following biological activities in LPS-responsive C3H/HeN mice and LPS-hyporesponsive C3H/HeJ mice: lethal toxicity in GalN-sensitized mice, in vitro induction of tumor necrosis factor- and NO production by macrophages, and mitogen-activated protein kinase activation in macrophages. The macrophage activation by CAZ-released endotoxin as well as LPS was mainly dependent on the presence of serum factor and CD14 antigen. Polymyxin B blocked the activity. These findings indicate that the endotoxic activity of CAZ-released endotoxin is due primarily to LPS (lipid A).
Modulation of Gyrase-Mediated DNA Cleavage and Cell Killing by ATP
Authors: Li Tsai-Kun , Liu Leroy F. 
Published: October 2018

ABSTRACT

An uncoupler of oxidative phosphorylation, 2,4-dinitrophenol, and an aconitase inhibitor, fluoroacetic acid, both of which are known to lower the cellular ATP pool, protected
Escherichia coli
cells from the bactericidal actions of gyrase poisons including quinolone antibiotics, nalidixic acid and ciprofloxacin, and the epipodophyllotoxins VP-16 and VM-26. Using purified
E. coli
DNA gyrase, we examined the effect of ATP on gyrase-mediated DNA cleavage in the presence of these gyrase poisons. ATP was shown to stimulate gyrase-mediated DNA cleavage from 10- to more than 100-fold in the presence of these gyrase poisons. ADP antagonized the stimulatory effect of ATP. Consequently, gyrase-mediated DNA cleavage induced by gyrase poisons is modulated by the ATP concentration/ADP concentration ([ATP]/[ADP]) ratio. Coumermycin A1, an inhibitor of the ATPase subunit of DNA gyrase, like ADP, also effectively antagonized the stimulatory effect of ATP on gyrase-mediated DNA cleavage induced by gyrase poisons. Furthermore, coumermycin A1, like DNP and fluoroacetic acid, also protected cells from the bactericidal action of gyrase poisons. In the aggregate, our results are consistent with the notion that the [ATP]/[ADP] ratio, through its modulatory effect on the gyrase-mediated DNA cleavage, is an important determinant of cellular susceptibility to gyrase poisons.
In Vitro Activities of Benzimidazoles against
Echinococcus multilocularis
Metacestodes
Authors: Jura Heike , Bader Augustinus , Frosch Matthias 
Published: October 2018

ABSTRACT

Alveolar echinococcosis, caused by the larval (metacestode) stage of the tapeworm
Echinococcus multilocularis
, is a lethal parasitosis of the liver prevalent in the Northern Hemisphere. For chemotherapy the benzimidazole derivatives mebendazole and albendazole were introduced, and their use has resulted in a significant improvement in the survival rates. However, data from experiments with animals and clinical observations indicate that these drugs elicit only parasitostatic activity and in most cases are not able to completely eliminate the parasitic metacestode tissue. In the present study, we applied a culture system for the in vitro growth and proliferation of
E. multilocularis
metacestodes to analyze the parasitostatic and parasitocidal potential of mebendazole. Here, we demonstrate for the first time that at concentrations of >0.1 μM, i.e., at concentrations used for therapy of human alveolar echinococcosis, this antihelminth drug is parasitocidal in vitro. Viability assessment was performed by infection experiments with
Meriones unguiculatus
and mebendazole-treated metacestode tissue and by reverse transcription-PCR for the detection of
E. multilocularis
mRNA. The
E. multilocularis
in vitro model proved to be a valuable tool for the analysis of the potential of antihelminth drugs.
Chromosomally Encoded AmpC-Type β-Lactamase in a Clinical Isolate of
Proteus mirabilis
Authors: Bret L. , Chanal-Claris C. , Sirot D. , Chaibi E. B. , Labia R. , Sirot J. 
Published: October 2018

ABSTRACT

A clinical strain of
Proteus mirabilis
(CF09) isolated from urine specimens of a patient displayed resistance to amoxicillin (MIC >4,096 μg/ml), ticarcillin (4,096 μg/ml), cefoxitin (64 μg/ml), cefotaxime (256 μg/ml), and ceftazidime (128 μg/ml) and required an elevated MIC of aztreonam (4 μg/ml). Clavulanic acid did not act synergistically with cephalosporins. Two β-lactamases with apparent pIs of 5.6 and 9.0 were identified by isoelectric focusing on a gel. Substrate and inhibition profiles were characteristic of an AmpC-type β-lactamase with a pI of 9.0. Amplification by PCR with primers for
ampC
genes (
Escherichia coli
,
Enterobacter cloacae
, and
Citrobacter freundii
) of a 756-bp DNA fragment from strain CF09 was obtained only with
C. freundii
-specific primers. Hybridization results showed that the
ampC
gene is only chromosomally located while the
TEM
gene is plasmid located. After cloning of the gene, analysis of the complete nucleotide sequence (1,146 bp) showed that this
ampC
gene is close to
bla
CMY-2
, from which it differs by three point mutations leading to amino acid substitutions Glu → Gly at position 22, Trp → Arg at position 201, and Ser → Asn at position 343. AmpC β-lactamases derived from that of
C. freundii
(LAT-1, LAT-2, BIL-1, and CMY-2) have been found in
Klebsiella pneumoniae
,
E. coli
, and
Enterobacter aerogenes
and have been reported to be plasmid borne. This is the first example of a chromosomally encoded AmpC-type β-lactamase observed in
P. mirabilis
. We suggest that it be designated CMY-3.
Interactions of β-Lactamases with Sanfetrinem (GV 104326) Compared to Those with Imipenem and with Oral β-Lactams
Authors: Babini Gioia S. , Yuan Meifang , Livermore David M. 
Published: October 2018

ABSTRACT

Sanfetrinem is a trinem β-lactam which can be administered orally as a hexatil ester. We examined whether its β-lactamase interactions resembled those of the available carbapenems, i.e., stable to AmpC and extended-spectrum β-lactamases but labile to class B and functional group 2f enzymes. The comparator drugs were imipenem, oral cephalosporins, and amoxicillin. MICs were determined for β-lactamase expression variants, and hydrolysis was examined directly with representative enzymes. Sanfetrinem was a weak inducer of AmpC β-lactamases below the MIC and had slight lability, with a
k
cat
of 0.00033 s
−1
for the
Enterobacter cloacae
enzyme. Its MICs for AmpC-derepressed
E. cloacae
and
Citrobacter freundii
were 4 to 8 μg/ml, compared with MICs of 0.12 to 2 μg/ml for AmpC-inducible and -basal strains; MICs for AmpC-derepressed
Serratia marcescens
and
Morganella morganii
were not raised. Cefixime and cefpodoxime were more labile than sanfetrinem to the
E. cloacae
AmpC enzyme, and AmpC-derepressed mutants showed much greater resistance; imipenem was more stable and retained full activity against derepressed mutants. Like imipenem, sanfetrinem was stable to TEM-1 and TEM-10 enzymes and retained full activity against isolates and transconjugants with various extended-spectrum TEM and SHV enzymes, whereas these organisms were resistant to cefixime and cefpodoxime. Sanfetrinem, like imipenem and cefixime but unlike cefpodoxime, also retained activity against
Proteus vulgaris
and
Klebsiella oxytoca
strains that hyperproduced potent chromosomal class A β-lactamases. Functional group 2f enzymes, including Sme-1, NMC-A, and an unnamed enzyme from
Acinetobacter
spp., increased the sanfetrinem MICs by up to 64-fold. These enzymes also compromised the activities of imipenem and amoxicillin but not those of the cephalosporins. The hydrolysis of sanfetrinem was examined with a purified Sme-1 enzyme, and biphasic kinetics were found. Finally, zinc β-lactamases, including IMP-1 and the L1 enzyme of
Stenotrophomonas maltophilia
, conferred resistance to sanfetrinem and all other β-lactams tested, and hydrolysis was confirmed with the IMP-1 enzyme. We conclude that sanfetrinem has β-lactamase interactions similar to those of the available carbapenems except that it is a weaker inducer of AmpC types, with some tendency to select derepressed mutants, unlike imipenem and meropenem.
Influence of Test Conditions on Antifungal Time-Kill Curve Results: Proposal for Standardized Methods
Authors: Klepser Michael E. , Ernst Erika J. , Lewis Russell E. , Ernst Michael E. , Pfaller Michael A. 
Published: October 2018

ABSTRACT

This study was designed to examine the effects of antifungal carryover, agitation, and starting inoculum on the results of time-kill tests conducted with various
Candida
species. Two isolates each of
Candida albicans
,
Candida tropicalis
, and
Candida glabrata
were utilized. Test antifungal agents included fluconazole, amphotericin B, and LY303366. Time-kill tests were conducted in RPMI 1640 medium buffered with morpholinepropanesulfonic acid (MOPS) to a pH of 7.0 and incubated at 35°C. Prior to testing, the existence of antifungal carryover was evaluated at antifungal concentrations ranging from 1× to 16× MIC by four plating methods: direct plating of 10, 30, and 100 μl of test suspension and filtration of 30 μl of test suspension through a 0.45-μm-pore-size filter. Time-kill curves were performed with each isolate at drug concentrations equal to 2× MIC, using a starting inoculum of approximately 10
5
CFU/ml, and incubated with or without agitation. Last, inoculum experiments were conducted over three ranges of starting inocula: 5 × 10
2
to 1 × 10
4
, >1 × 10
4
to 1 × 10
6
, and >1 × 10
6
to 1 × 10
8
CFU/ml. Significant antifungal carryover (>25% reduction in CFU/milliliter from the control value) was observed with amphotericin B and fluconazole; however, carryover was eliminated with filtration. Agitation did not appreciably affect results. The starting inoculum did not significantly affect the activity of fluconazole or amphotericin B; however, the activity of LY303366 may be influenced by the starting inoculum. Before antifungal time-kill curve methods are routinely employed by investigators, methodology should be scrutinized and standardized procedures should be developed.
Pharmacokinetics of a New Carbapenem, DA-1131, after Intravenous Administration to Rats with Uranyl Nitrate-Induced Acute Renal Failure
Authors: Kim So H. , Shim Hyun J. , Kim Won B. , Lee Myung G. 
Published: October 2018

ABSTRACT
Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug (50 mg/kg of body weight) to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF rats). The impaired kidney function was observed in U-ARF rats on the basis of physiological parameters observed by microscopy of the kidney and obtained by chemical analysis of the plasma. After a 1-min intravenous infusion of DA-1131, the concentrations in plasma and the total area under the plasma concentration-time curve from time zero to time infinity increased significantly in U-ARF rats compared with those in control rats (13,000 versus 4,400 μg · min/ml). This was due to the significantly slower total body clearance (CL) of DA-1131 (3.84 versus 11.4 ml/min/kg) from U-ARF rats than from control rats. The significantly slower CL of DA-1131 from U-ARF rats was due to both significantly slower renal clearance (0.000635 versus 4.95 ml/min/kg because of a significant decrease in the 8-h urinary excretion of unchanged DA-1131 [1.54 versus 43.8% of the intravenous dose] due to impaired kidney function, as proved by the significant decrease in creatinine clearance [0.0159 versus 4.29 ml/min/kg]) and significantly slower nonrenal clearance (3.80 versus 6.34 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney) in U-ARF rats. The amounts of DA-1131 recovered from all tissues studied (except the kidneys) were significantly higher for U-ARF rats than for control rats; however, the ratios of the amount in tissue to the concentration in plasma (except those for the kidney, small intestine, and spleen) were not significantly different between the two groups of rats, indicating that the affinity of DA-1131 for rat tissues was not changed considerably in U-ARF rats.
Alterations in PBP 1A Essential for High-Level Penicillin Resistance in
Streptococcus pneumoniae
Authors: Smith Anthony M. , Klugman Keith P. 
Published: October 2018

ABSTRACT
High-level penicillin resistance in pneumococci is due to alterations in penicillin-binding proteins (PBPs) 2X, 2B, and 1A. We have sequenced the penicillin-binding domain of PBP 1A from penicillin-resistant South African pneumococcal isolates and have identified amino acid substitutions which are common to all the resistant isolates analyzed. Site-directed mutagenesis was then used to determine whether particular amino acid substitutions at specific positions in PBP 1A mediate penicillin resistance. PCR was used to isolate PBP 2X, 2B, and 1A genes from clinical isolate 8303 (penicillin MIC, 4 μg/ml). These wild-type PBP genes were cloned into pGEM-3Zf and were used as the transforming DNA. Susceptible strain R6 (MIC, 0.015 μg/ml) was first transformed with PBP 2X and 2B DNA, resulting in PBP 2X/2B-R6 transformants for which MICs were 0.25 μg/ml. When further transformed with PBP 1A DNA, 2X/2B/1A-R6 transformants for which MICs were 1.5 μg/ml were obtained. Site-directed mutagenesis of the PBP 1A gene from isolate 8303 was then used to reverse particular amino acid substitutions, followed by transformation of PBP 2X/2B-R6 transformants with the mutagenized PBP 1A DNA. For PBP 2X/2B/1A-R6 transformants, the introduction of the reversal of Thr-371 by Ser or Ala in PBP 1A decreased the MIC from 1.5 to 0.5 μg/ml, whereas the reversal of four consecutive amino acid substitutions (Thr-574 by Asn, Ser-575 by Thr, Gln-576 by Gly, and Phe-577 by Tyr) decreased the MIC from 1.5 to 0.375 μg/ml. These data reveal that amino acid residue 371 and residues 574 to 577 of PBP 1A are important positions in PBP 1A with respect to the interaction with penicillin and the development of resistance.