bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secretion of Sparfloxacin from the Human Intestinal Caco-2 Cell Line Is Altered by P-Glycoprotein Inhibitors
Authors: Cormet-Boyaka Estelle , Huneau Jean-François , Mordrelle Agnès , Boyaka Prosper N. , Carbon Claude , Rubinstein Ethan , Tomé Daniel 
Published: October 2018

ABSTRACT
The mechanism of intestinal secretion of the difluorinated quinolone sparfloxacin was investigated with the epithelial cell line Caco-2 and was compared to that of the P-glycoprotein (P-gp) substrate vinblastine. The P-gp inhibitors verapamil and progesterone significantly increased the epithelial cell accumulation of both vinblastine and sparfloxacin. This increase is likely to result from an inhibition of drug secretion since both vinblastine uptake and sparfloxacin uptake are known to proceed through a passive transmembrane diffusion. The unidirectional fluxes across cell monlayers grown on permeable filters indicated that a net secretion of sparfloxacin and vinblastine occurred across Caco-2 cells. These secretions were significantly inhibited by the MDR-reversing agent verapamil. We conclude that the P-gp is likely to be involved in the intestinal elimination of the difluorinated quinolone sparfloxacin.
Inhibitory Activities of Gatifloxacin (AM-1155), a Newly Developed Fluoroquinolone, against Bacterial and Mammalian Type II Topoisomerases
Authors: Takei Masaya , Fukuda Hideyuki , Yasue Tokutaro , Hosaka Masaki , Oomori Yasuo 
Published: October 2018

ABSTRACTWe determined the inhibitory activities of gatifloxacin againstStaphylococcus aureustopoisomerase IV,Escherichia coliDNA gyrase, and HeLa cell topoisomerase II and compared them with those of several quinolones. The inhibitory activities of quinolones against these type II topoisomerases significantly correlated with their antibacterial activities or cytotoxicities (correlation coefficient [r] = 0.926 forS. aureus,r= 0.972 forE. coli, andr= 0.648 for HeLa cells). Gatifloxacin possessed potent inhibitory activities against bacterial type II topoisomerases (50% inhibitory concentration [IC50] = 13.8 μg/ml forS. aureustopoisomerase IV; IC50= 0.109 μg/ml forE. coliDNA gyrase) but the lowest activity against HeLa cell topoisomerase II (IC50= 265 μg/ml) among the quinolones tested. There was also a significant correlation between the inhibitory activities of quinolones againstS. aureustopoisomerase IV and those againstE. coliDNA gyrase (r= 0.969). However, the inhibitory activity against HeLa cell topoisomerase II did not correlate with that against either bacterial enzyme. The IC50of gatifloxacin for HeLa cell topoisomerase II was 19 and was more than 2,400 times higher than that forS. aureustopoisomerase IV and that forE. coliDNA gyrase. These ratios were higher than those for other quinolones, indicating that gatifloxacin possesses a higher selectivity for bacterial type II topoisomerases.
Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution and Effect of Food
Authors: Abdel-Rahman Susan M. , Kearns Gregory L. 
Published: October 2018

ABSTRACT

Pleconaril is an orally active broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. We report the results of a randomized two-way crossover study designed to characterize the disposition of a single dose (200 mg) of pleconaril oral solution in fed and fasting humans. Twelve healthy adult subjects (18.7 to 39 years of age) participated in this study. Each subject received a single 200-mg dose of pleconaril oral solution, both coadministered with a standard English breakfast and following a 10-h predose fast. There was a minimum 7-day washout period between pleconaril doses. Repeated blood samples (
n
= 10) were obtained over 24 h postdose, and the pleconaril level in plasma was quantified by gas chromatography. Plasma concentration-versus-time data were curve fitted for each subject by using a nonlinear weighted least-squares algorithm, and pharmacokinetic parameters were determined from the polyexponential estimates. Pleconaril disposition was best characterized by a one-compartment open model with first-order absorption. The apparent bioavailability of pleconaril oral solution was significantly increased with the administration of food. The area under the concentration-time curve and maximum concentration of pleconaril in plasma achieved following the standard English breakfast (i.e., 9.08 ± 3.23 mg/liter · h and 1.14 ± 0.58 mg/liter, respectively) were 2.2- and 2.5-fold higher, respectively than those achieved in the fasting state (i.e., 4.08 ± 2.74 mg/liter · h and 0.46 ± 0.30 mg/liter, respectively). Mean plasma pleconaril concentrations 12 h after a single 200-mg oral dose (fed, 0.25 ± 0.2 mg/liter; fasting, 0.11 ± 0.10 mg/liter) in healthy adults remained greater than that required to inhibit more than 90% of the enteroviruses in cell culture (i.e., 0.07 mg/liter). To enhance the oral bioavailability of pleconaril, coadministration with a fat-containing meal is recommended.
Enhancement of Antimicrobial Activity of Neuropeptide Y by N-Terminal Truncation
Authors: Shimizu Mayumi , Shigeri Yasushi , Tatsu Yoshiro , Yoshikawa Susumu , Yumoto Noboru 
Published: October 2018

ABSTRACT

The activity of neuropeptide Y (NPY) against
Candida albicans
, which was revealed to be fungicidal, was enhanced significantly by the truncation of amino acid residues at the N terminus. The most active peptides (MICs, approximately 1 μM) were about 10-fold more potent than the intact NPY (MIC, approximately 10 μM). The enhancement was weakened by the replacement of the N terminus by negatively charged residues and/or acylation of the α-amino group. These results suggest that only the α-helical region of NPY is necessary for the antimicrobial activity and that the net charge of the peptide is important for the activity.
Pharmacokinetic Interaction between Ritonavir and Indinavir in Healthy Volunteers
Authors: Hsu Ann , Granneman G. Richard , Cao Guoliang , Carothers Lori , Japour Anthony , El-Shourbagy Tawakol , Dennis Suzana , Berg Jeanne , Erdman Keith , Leonard John M. , Sun Eugene 
Published: October 2018

ABSTRACT

The pharmacokinetic interaction between indinavir and ritonavir was evaluated in five groups of healthy adult volunteers to explore the potential for twice-daily (b.i.d.) dosing of this combination. All subjects received 800 mg of indinavir every 8 h (q8h) on day 2. In addition, subjects in group I received one dose of 800 mg of indinavir on day 1 and 800 mg of indinavir q8h on day 17. Subjects in Groups II and IV each received one dose of 600 mg of indinavir on days 1 and 17, and subjects in groups III and V each received one dose of 400 mg of indinavir on days 1 and 17. During days 3 to 17, ritonavir placebo or ritonavir at 200, 300, 300, or 400 mg q12h was given to groups I, II, III, IV, and V, respectively. Ritonavir at steady state probably inhibited the cytochrome P-450 3A metabolism of indinavir and substantially increased plasma indinavir concentrations, with the area under the plasma concentration-time curve (AUC) increasing up to 475% and the peak concentration in serum (
C
max
) increasing up to 110%. The
C
max
/trough concentration ratio decreased from 50 in standard q8h regimens to less than 14 when indinavir was administered with ritonavir. For a constant indinavir dose, an increase in the ritonavir dose yielded similar indinavir AUCs,
C
max
s, and concentrations at 12 h (
C
12
s). For a constant ritonavir dose, an increase in the indinavir dose resulted in approximately proportional increases in the indinavir AUC, less than proportional increases in
C
max
, and slightly more than proportional increases in
C
12
. Ritonavir reduced between-subject variability in the indinavir AUC and trough concentrations and did not affect indinavir renal clearance. With the altered pharmacokinetic profile, indinavir likely could be given as a b.i.d. combination regimen with ritonavir. This could potentially improve patient compliance and thereby reduce treatment failures.
In Vitro Selection of Resistance to Four β-Lactams and Azithromycin in
Streptococcus pneumoniae
Authors: Pankuch Glenn A. , Jueneman Shane A. , Davies Todd A. , Jacobs Michael R. , Appelbaum Peter C. 
Published: October 2018

ABSTRACT

Selection of resistance to amoxicillin (with or without clavulanate), cefaclor, cefuroxime, and azithromycin among six penicillin G- and azithromycin-susceptible pneumococcal strains and among four strains with intermediate penicillin sensitivities (azithromycin MICs, 0.125 to 4 μg/ml) was studied by performing 50 sequential subcultures in medium with sub-MICs of these antimicrobial agents. For only one of the six penicillin-susceptible strains did subculturing in medium with amoxicillin (with or without clavulanate) lead to an increased MIC, with the MIC rising from 0.008 to 0.125 μg/ml. Five of the six penicillin-susceptible strains showed increased azithromycin MICs (0.5 to >256.0 μg/ml) after 17 to 45 subcultures. Subculturing in medium with cefaclor did not affect the cefaclor MICs of three strains but and led to increased cefaclor MICs (from 0.5 to 2.0 to 4.0 μg/ml) for three of the six strains, with MICs of other β-lactams rising 1 to 3 twofold dilutions. Subculturing in cefuroxime led to increased cefuroxime MICs (from 0.03 to 0.06 μg/ml to 0.125 to 0.5 μg/ml) for all six strains without significantly altering the MICs of other β-lactams, except for one strain, which developed an increased cefaclor MIC. Subculturing in azithromycin did not affect β-lactam MICs. Subculturing of the four strains with decreased penicillin susceptibility in amoxicillin (with or without clavulanate) or cefuroxime did not select for β-lactam resistance. Subculturing of one strain in cefaclor led to an increase in MIC from 0.5 to 2.0 μg/ml after 19 passages. In contrast to strains that were initially azithromycin susceptible, which required >10 subcultures for resistance selection, three of four strains with azithromycin MICs of 0.125 to 4.0 μg/ml showed increased MICs after 7 to 13 passages, with the MICs increasing to 16 to 32 μg/ml. All azithromycin-resistant strains were clarithromycin resistant. With the exception of strains that contained
mefE
at the onset, no strains that developed resistance to azithromycin contained
ermB
or
mefE
, genes that have been found in macrolide-resistant pneumococci obtained from clinic patients.
Fluoroquinolone Action against Mycobacteria: Effects of C-8 Substituents on Growth, Survival, and Resistance
Authors: Dong Yuzhi , Xu Chen , Zhao Xilin , Domagala John , Drlica Karl 
Published: October 2018

ABSTRACT

Fluoroquinolones trap gyrase on DNA as bacteriostatic complexes from which lethal DNA breaks are released. Substituents at the C-8 position increase activities of
N
-1-cyclopropyl fluoroquinolones against several bacterial species. In the present study, a C-8-methoxyl group improved bacteriostatic action against
gyrA
(gyrase-resistant) strains of
Mycobacterium tuberculosis
and
M. bovis
BCG. It also enhanced lethal action against gyrase mutants of
M. bovis
BCG. When cultures of
M. smegmatis
,
M. bovis
BCG, and
M. tuberculosis
were challenged with a C-8-methoxyl fluoroquinolone, no resistant mutant was recovered under conditions in which more than 1,000 mutants were obtained with a C-8-H control. A C-8-bromo substituent also increased bacteriostatic and lethal activities against a
gyrA
mutant of
M. bovis
BCG. When lethal activity was normalized to bacteriostatic activity, the C-8-methoxyl compound was more bactericidal than its C-8-H control, while the C-8-bromo fluoroquinolone was not. The C-8-methoxyl compound was also found to be more effective than the C-8-bromo fluoroquinolone at reducing selection of resistant mutants when each was compared to a C-8-H control over a broad concentration range. These data indicate that a C-8-methoxyl substituent, which facilitates attack of first-step gyrase mutants, may help make fluoroquinolones effective antituberculosis agents.
Intracellular Nucleotides of (−)-2′,3′-Deoxy-3′-Thiacytidine in Peripheral Blood Mononuclear Cells of a Patient Infected with Human Immunodeficiency Virus
Authors: Solas Caroline , Li Yu-Feng , Xie Meng-Yu , Sommadossi Jean-Pierre , Zhou Xiao-Jian 
Published: October 2018

ABSTRACT

An analytical methodology was developed to quantitate the intracellular nucleotides including mono-, di-, and triphosphates and the diphosphocholine derivative of (−)-2′,3′-deoxy-3′-thiacytidine (3TC) in human peripheral blood mononuclear cells (PBMCs). The procedure includes the resolution of 3TC nucleotides by solid-phase extraction (SPE) on an anion-exchange cartridge, with subsequent enzyme digestion of the resulting phosphates to the parent drug that is ultimately quantitated by high-performance liquid chromatography with UV detection (HPLC-UV). Validation was performed with PBMCs from healthy donors exposed to [
3
H]3TC, leading to the formation of intracellular nucleotides that were quantitated by anion-exchange HPLC with radioactive detection (HPLC-RA). These nucleotide levels served as reference values and were used for cross-validation with data obtained by HPLC-UV. An excellent correlation was established between the results obtained by HPLC-RA and those obtained by HPLC-UV, with a slope of the regression lines close to unity and intercepts near nullity as well as a correlation coefficient close to unity for all 3TC phosphates. The assay was characterized by a limit of quantitation below 1 ng (amount on column) with a precision (percentage of coefficient of variation of repeated measurement) ranging from 0.8 to 18.1% and an accuracy (deviation of the amount determined by HPLC-UV from the nominal reference value) varying from −14.8 to 19.4%. This methodology was successfully applied to determine the quantity of 3TC nucleotides in PBMCs of a patient infected with human immunodeficiency virus after oral administration of 3TC and stavudine.
Penetration of Clindamycin and Its Metabolite N -Demethylclindamycin into Cerebrospinal Fluid following Intravenous Infusion of Clindamycin Phosphate in Patients with AIDS
Authors: Gatti Giorgio , Malena Marina , Casazza Rosetta , Borin Marie , Bassetti Matteo , Cruciani Mario 
Published: October 2018

ABSTRACT

Clindamycin, which is usually used in combination with pyrimethamine, has been proven effective in the treatment of cerebral toxoplasmosis in human immunodeficiency virus-infected patients. However, it is not known if clindamycin achieves inhibitory concentrations at the site of infection. Also, it has been hypothesized that the activity of clindamycin against
Toxoplasma gondii
may be due, at least in part, to a metabolite. We evaluated the penetration of clindamycin and its major metabolite,
N
-demethylclindamycin (NDC), into cerebrospinal fluid (CSF) of AIDS patients undergoing lumbar puncture for diagnostic purposes. A single, 1,200-mg dose of clindamycin was administered as a 45-min intravenous infusion beginning at 1.5 or 2.5 h before CSF sampling. The concentrations of clindamycin in CSF ranged from 0.091 to 0.429 mg/liter at 1.5 h and from 0.120 to 0.283 mg/liter at 2.5 h following the beginning of the infusion. The concentrations of clindamycin in CSF were well above the 50% inhibitory concentration of 0.001 mg/liter and the parasiticidal concentration of 0.006 mg/liter. NDC was undetectable both in plasma and in CSF. Our study provides a pharmacokinetic rationale for the clinical efficacy of clindamycin in the treatment of cerebral toxoplasmosis.
Coresistance to Zidovudine and Foscarnet Is Associated with Multiple Mutations in the Human Immunodeficiency Virus Type 1 Reverse Transcriptase
Authors: Tachedjian Gilda , French Martyn , Mills John 
Published: October 2018

ABSTRACT
Human immunodeficiency virus type 1 (HIV-1) isolates obtained from a patient with AIDS were assessed for coresistance to foscarnet and zidovudine. An HIV-1 strain (AP20) coresistant to foscarnet and zidovudine was isolated after 20 months of continuous combination therapy. The reverse transcriptase (RT) gene of AP20 had 41 substitutions which were different from the HXB2-D sequence and 9 that were different from the sequence of its foscarnet-sensitive, zidovudine-resistant progenitor virus (AP6). Six of these mutations were nonpolymorphic (T39A, V108I, K166R, K219R, K223Q, and L228R). Both strains had the conventional mutations mediating zidovudine resistance. In vivo selection may result in HIV-1 strains that are coresistant to foscarnet and zidovudine, but coresistance appears to require a complex evolutionary path and multiple RT mutations.
Antibiotic-Induced Release of Lipoteichoic Acid and Peptidoglycan from
Staphylococcus aureus
: Quantitative Measurements and Biological Reactivities
Authors: van Langevelde P. , van Dissel J. T. , Ravensbergen E. , Appelmelk B. J. , Schrijver I. A. , Groeneveld P. H. P. 
Published: October 2018

ABSTRACT

Antibiotics with different mechanisms of action may vary with respect to their effects on the release and immunostimulatory activities of cell wall fragments from gram-positive bacteria. Therefore, after
Staphylococcus aureus
was cultured for 4 h in the absence of antibiotics (control) and in the presence of β-lactam antibiotics (imipenem, flucloxacillin, or cefamandole) and protein synthesis-inhibiting antibiotics (erythromycin, clindamycin, or gentamicin), the lipoteichoic acid (LTA) and peptidoglycan (PG) levels in the bacterial supernatants were measured. β-Lactam antibiotics greatly enhanced the release of LTA and PG (4- to 9-fold and 60- to 85-fold, respectively), whereas protein synthesis inhibitors did not affect PG release and even inhibited the release of LTA compared to the amount of LTA released in control cultures. The capacity of β-lactam supernatants to stimulate the production of tumor necrosis factor alpha and interleukin-10 in human whole blood was significantly higher than that of protein synthesis inhibitor or control supernatants; the amounts of these cytokines released were directly proportional to the concentrations of PG and LTA in the supernatants. Enzymatic degradation of PG in the supernatants indicated that PG was mainly responsible for the observed biological reactivity.
Photosensitivity Reactions Caused by Lomefloxacin Hydrochloride: A Multicenter Survey
Authors: Arata Jirô , Horio Takeshi , Soejima Rinzo , Ohara Kenji 
Published: October 2018

ABSTRACT
The photosensitivity effect of lomefloxacin hydrochloride (LFLX) was investigated in terms of patient background factors (sex, age, underlying disease, complications, history, occupation, and residential condition, etc.), treatment factors (daily dosage of LFLX, duration of treatment, total dose, concomitant drugs, and previous medication, etc.), and correlations among them. In 100 institutions throughout Japan, 4,284 patients were enrolled over a period of 2 years, beginning in October 1991, avoiding the accumulation of patients in any specific season. Since 8 patients did not visit again after enrollment, the clinical records of 4,276 patients were analyzed. Photosensitivity in 44 patients was found (1.03%), but the symptoms in most patients were not severe and improved after discontinuation of LFLX treatment. The photosensitivity reaction was more prevalent in patients who were 60 years of age and older with concomitant diseases and complications, in patients treated with a total amount of 20 g and more of LFLX for 30 days or longer, and in patients with a history of previous treatment with quinolone drugs. Although the incidence and degree of the photosensitivity reaction vary significantly among new quinolone drugs, every quinolone drug is potentially phototoxic. In particular, long-term use of LFLX should be avoided, and patients taking LFLX should be advised to abstain from prolonged exposure to sunlight.
Rapid Emergence of High-Level Resistance to Quinolones in
Campylobacter jejuni
Associated with Mutational Changes in
gyrA
and
parC
Authors: Gibreel Amera , Sjögren Eva , Kaijser Bertil , Wretlind Bengt , Sköld Ola 
Published: October 2018

ABSTRACT

Quinolone resistance in clinical isolates of
Campylobacter jejuni
in Sweden increased more than 20-fold at the beginning of the 1990s. Resistance to 125 μg of ciprofloxacin per ml in clinical isolates was associated with chromosomal mutations in
C. jejuni
leading to a Thr-86-Ile substitution in the
gyrA
product and a Arg-139-Gln substitution in the
parC
product.
Joint Tolerance to β-Lactam and Fluoroquinolone Antibiotics in
Escherichia coli
Results from Overexpression of
hipA
Authors: Falla Timothy J. , Chopra Ian 
Published: October 2018

ABSTRACT

The basis of joint tolerance to β-lactam and fluoroquinolone antibiotics in
Escherichia coli
mediated by
hipA
was examined. An antibiotic tolerance phenotype was produced by overexpression of
hipA
under conditions that did not affect the growth rate of the organism. Overexpressing
hipA
probably decreases the period in which bacteria are susceptible to the antibiotics by temporarily affecting some aspect of chromosome replication or cell division.
Effects of Bicyclomycin on RNA- and ATP-Binding Activities of Transcription Termination Factor Rho
Authors: Carrano Lucia , Bucci Cecilia , De Pascalis Roberto , Lavitola Alfredo , Manna Filomena , Corti Emiliana , Bruno Bruni Carmelo , Alifano Pietro 
Published: October 2018

ABSTRACT

Bicyclomycin is a commercially important antibiotic that has been shown to be effective against many gram-negative bacteria. Genetic and biochemical evidence indicates that the antibiotic interferes with RNA metabolism in
Escherichia coli
by inhibiting the activity of transcription termination factor Rho. However, the precise mechanism of inhibition is not completely known. In this study we have used in vitro transcription assays to analyze the effects of bicyclomycin on the termination step of transcription. The Rho-dependent transcription termination region located within the
hisG
cistron of
Salmonella typhimurium
has been used as an experimental system. The possible interference of the antibiotic with the various functions of factor Rho, such as RNA binding at the primary site, ATP binding, and hexamer formation, has been investigated by RNA gel mobility shift, photochemical cross-linking, and gel filtration experiments. The results of these studies demonstrate that bicyclomycin does not interfere with the binding of Rho to the loading site on nascent RNA. Binding of the factor to ATP is not impeded, on the contrary, the antibiotic appears to decrease the apparent equilibrium dissociation constant for ATP in photochemical cross-linking experiments. The available evidence suggests that this decrease might be due to an interference with the correct positioning of ATP within the nucleotide-binding pocket leading b an inherent block of ATP hydrolysis. Possibly, as a consequence of this interference, the antibiotic also prevents ATP-dependent stabilization of Rho hexamers.
In Vitro Activity of BAY 12-8039, a New Fluoroquinolone, against Mycoplasmas
Authors: Bébéar C. M. , Renaudin H. , Boudjadja A. , Bébéar C. 
Published: October 2018

ABSTRACT

The in vitro activity of the fluoroquinolone BAY 12-8039 against 66 strains of different mycoplasma species and 30 strains of
Ureaplasma urealyticum
was compared with those of three other antimicrobial agents. BAY 12-8039 at 0.5 μg/ml inhibited 100% of all the mycoplasmal and ureaplasmal strains tested. The minimal bactericidal concentrations of BAY 12-8039 increased only two- to eightfold compared to the MICs. Furthermore, they were comparable to those of sparfloxacin and lower than those of doxycycline and clarithromycin.