bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chondrotoxicity and Toxicokinetics of Sparfloxacin in Juvenile Rats
Authors: Stahlmann Ralf , Zippel Uta , Förster Christian , Schwabe Rudolf , Shakibaei Mehdi , Merker Hans-Joachim , Borner Klaus 
Published: October 2018

ABSTRACT

Sparfloxacin is a fluoroquinolone with improved antibacterial activity against gram-positive pathogens. Like other quinolones, use of this drug is contraindicated in children and adolescents because of its potential chondrotoxicity in juveniles. We performed histological and immunohistochemical studies on the knee joint cartilage in 5-week-old rats after treatment with 600 or 1,800 mg of sparfloxacin/kg of body weight. Treatment with single or multiple oral doses of 600 mg of sparfloxacin/kg was not sufficient to induce joint cartilage lesions. However, five of eight rats treated with a single oral dose of 1,800 mg of sparfloxacin/kg of body weight showed typical cartilage lesions in the femoral part of the knee joint. The concentrations of the drug in plasma measured 0.25, 0.75, 1.5, 3, 6, 12, and 24 h after the administration of an oral dose of 600 mg of sparfloxacin/kg were 6.3 ± 1.8, 9.2 ± 1.7, 9.6 ± 2.7, 13.0 ± 1.8, 12.3 ± 1.6, 3.4 ± 0.4, and 0.30 ± 0.20 mg/liter, respectively (mean ± standard deviation [SD];
n
= 5 to 6 per group). The concentrations in plasma measured 0.75, 1.5, 3, 6, 24, and 48 h after the administration of an oral dose of 1,800 mg of sparfloxacin/kg were 10.9 ± 1.5, 15.9 ± 1.6, 19.1 ± 1.7, 14.9 ± 3.1, 4.1 ± 0.6, and 0.46 ± 0.37 mg/liter, respectively (mean ± SD;
n
= 3 to 4 per group). The concentrations of sparfloxacin in joint cartilage were significantly higher at all time points studied (114.8 ± 80, 99.4 ± 31.5, 84.9 ± 16.8, 44.4 ± 13.9, and 14.2 ± 4.8 mg of sparfloxacin/kg at 1.5, 3, 6, 24, and 48 h after the administration of 1,800 mg/kg, respectively). The range of concentrations in bone were similar to the range of concentrations in cartilage (peak, 115 ± 12 mg/kg after 3 h). Our data indicate that chondrotoxic doses of sparfloxacin in juvenile rats are approximately 300 times higher than the doses of sparfloxacin used therapeutically (1,800 versus approximately 6 mg/kg of body weight), but due to species differences in kinetics, concentrations in plasma differ by a factor of only approximately 15. More data on quinolone concentrations in cartilage from animals and humans could provide a better basis for a reasonable risk assessment.
Roxithromycin Inhibits Cytokine Production by and Neutrophil Attachment to Human Bronchial Epithelial Cells In Vitro
Authors: Kawasaki Shin , Takizawa Hajime , Ohtoshi Takayuki , Takeuchi Naonobu , Kohyama Tadashi , Nakamura Hidenori , Kasama Tsuyoshi , Kobayashi Kazuo , Nakahara Kazuhiko , Morita Yutaka , Yamamoto Kazuhiko 
Published: October 2018

ABSTRACTWe evaluated the effect of roxithromycin on cytokine production and neutrophil attachment to human airway epithelial cells. Roxithromycin suppressed production of interleukin 8 (IL-8), IL-6, and granulocyte-macrophage colony-stimulating factor. It inhibited neutrophil adhesion to epithelial cells. Roxithromycin modulates local recruitment and activation of inflammatory cells, which may have relevance to its efficacy in airway diseases.
Glucuronidation of 3′-Azido-3′-Deoxythymidine (Zidovudine) by Human Liver Microsomes: Relevance to Clinical Pharmacokinetic Interactions with Atovaquone, Fluconazole, Methadone, and Valproic Acid
Authors: Trapnell Carol Braun , Klecker Raymond W. , Jamis-Dow Carlos , Collins Jerry M. 
Published: October 2018

ABSTRACT
Zidovudine (3′-azido-3′-deoxythymidine [AZT]), an antiviral nucleoside analog effective in the treatment of human immunodeficiency virus infection, is primarily metabolized to an inactive glucuronide form, GAZT, via uridine-5′-diphospho-glucuronosyltransferase (UGT) enzymes. UGT enzymes exist as different isoforms, each exhibiting substrate specificity. Published clinical studies have shown that atovaquone, fluconazole, methadone, and valproic acid decreased GAZT formation, presumably due to UGT inhibition. The effect of these drugs on AZT glucuronidation was assessed in vitro by using human hepatic microsomes to begin understanding in vitro-in vivo correlations for UGT metabolism. The concentrations of each drug studied were equal to those reported with the usual clinical doses and at concentrations at least 10 times higher than would be expected with these doses. High-performance liquid chromatography was used to assess the respective metabolism and formation of AZT and GAZT. All four drugs exhibited concentration-dependent inhibition of AZT glucuronidation. The respective concentrations of atovaquone and methadone which caused 50% inhibition of GAZT were >100 and 8 μg/ml, well above their usual clinical concentrations. Fluconazole and valproic acid exhibited 50% inhibition of GAZT at 50 and 100 μg/ml, which are within the clinical ranges of 10 to 100 and 50 to 100 μg/ml, respectively. These data suggest that inhibition of AZT glucuronidation may be more clinically significant with concomitant fluconazole and valproic acid. Factors such as inter- and intraindividual pharmacokinetic variability and changes in AZT intracellular concentrations should be considered as other mechanisms responsible for changes in AZT pharmacokinetics with concomitant therapies.
Effects of DU-6859a, a New Quinolone Antimicrobial, on Theophylline Metabolism in In Vitro and In Vivo Studies
Authors: Niki Yoshihito , Itokawa Kenichi , Okazaki Osamu 
Published: October 2018

ABSTRACT
In vitro and in vivo studies were conducted to investigate the drug interaction between a new quinolone antimicrobial, DU-6859a, and theophylline (TP). The effect of DU-6859a on TP metabolism was evaluated in vitro by measuring the rate of TP metabolite formation by using human liver microsomes. DU-6859a inhibited the metabolism of TP, especially the formation of 1-methylxanthine, in vitro, but to a lesser extent than other drugs that are known to interact with TP. TP was administered alone (200 mg twice a day [b.i.d.] for 9 days) or in combination with DU-6859a (50 or 100 mg b.i.d. for 5 days) to six healthy subjects. DU-6859a administered at a dose of 50 mg resulted in no changes in serum TP concentrations, and slight increases in serum TP concentrations were observed at a dose of 100 mg. Moreover, the administration of 100 mg of DU-6859a resulted in decreases in all urinary TP metabolites, with significant differences. It appears that although DU-6859a has a weak inhibitory effect on TP metabolism in vitro, its concomitant use with TP at clinical dosage levels does not cause any adverse effects, showing only a slight increase in blood TP concentrations and a decrease in urinary metabolites.
Characterization of a Staphylococcal Plasmid Related to pUB110 and Carrying Two Novel Genes,
vatC
and
vgbB
, Encoding Resistance to Streptogramins A and B and Similar Antibiotics
Authors: Allignet Jeanine , Liassine Nadia , El Solh Névine 
Published: October 2018

ABSTRACT

We isolated and sequenced a plasmid, named pIP1714 (4,978 bp), which specifies resistance to streptogramins A and B and the mixture of these compounds. pIP1714 was isolated from a
Staphylococcus cohnii
subsp.
cohnii
strain found in the environment of a hospital where pristinamycin was extensively used. Resistance to both compounds and related antibiotics is encoded by two novel, probably cotranscribed genes, (i)
vatC
, encoding a 212-amino-acid (aa) acetyltransferase that inactivates streptogramin A and that exhibits 58.2 to 69.8% aa identity with the Vat, VatB, and SatA proteins, and (ii)
vgbB
, encoding a 295-aa lactonase that inactivates streptogramin B and that shows 67% aa identity with the Vgb lactonase. pIP1714 includes a 2,985-bp fragment also found in two rolling-circle replication and mobilizable plasmids, pUB110 and pBC16, from gram-positive bacteria. In all three plasmids, the common fragment was delimited by two direct repeats of four nucleotides (GGGC) and included (i) putative genes closely related to
repB
, which encodes a replication protein, and to
pre
(
mob
), which encodes a protein required for conjugative mobilization and site-specific recombination, and (ii) sequences very similar to the double- and single-strand origins (
dso
,

sso
U

) and the recombination site, RS
A
. The antibiotic resistance genes
repB
and
pre
(
mob
) carried by each of these plasmids were found in the same transcriptional orientation.
In Vivo Antibacterial Activities of Sanfetrinem Cilexetil, a New Oral Tricyclic Antibiotic
Authors: Tamura Shinobu , Miyazaki Shuichi , Tateda Kazuhiro , Ohno Akira , Ishii Yoshikazu , Matsumoto Tetsuya , Furuya Nobuhiko , Yamaguchi Keizo 
Published: October 2018

ABSTRACT

The in vivo antibacterial activities of a new oral trinem, sanfetrinem cilexetil (a prodrug of sanfetrinem), were evaluated in comparison with those of cefdinir and amoxicillin. Sanfetrinem cilexetil showed potent efficacy against experimental murine septicemia caused by
Staphylococcus aureus
,
Streptococcus pyogenes
, and
Escherichia coli
and against murine respiratory infections caused by
Streptococcus pneumoniae
. Likewise, in murine models of respiratory infection by penicillin-susceptible and penicillin-resistant
S. pneumoniae
, sanfetrinem cilexetil was more effective than amoxicillin in reducing the number of bacteria in infected lungs. These results were reflected in its potent in vitro activity and high levels in plasma.
Immunomodulating Properties of the Antibiotic Novobiocin in Human Monocytes
Authors: Lührmann Anja , Thölke Jürgen , Behn Ingrid , Schumann Jens , Tiegs Gisa , Hauschildt Sunna 
Published: October 2018

ABSTRACTWe show that the coumeromycin antibiotic novobiocin, a potent inhibitor of ADP ribosylation, prevents lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-1), IL-6, and IL-10 secretion in human peripheral blood mononuclear cells. It shares these cytokine-suppressing properties with other inhibitors of ADP ribosylation. We found that novobiocin prevents TNF-α production by inhibiting translation of the TNF-α mRNA. Elevated TNF-α levels in mice treated withd-galactosamine (GalN)-LPS or GalN-TNF were not reduced by novobiocin; however, the drug exhibited hepatoprotective properties. Novobiocin causes downregulation of the surface molecules on monocytes, among which CD14 was the most affected. The diminished expression of surface molecules was not observed on T and B lymphocytes. Similar to other inhibitors of ADP ribosylation, novobiocin prevents LPS-induced phosphate labelling of γ-actins.
Molecular Cloning and Functional Analysis of a Novel Tetracycline Resistance Determinant,
tet
(V), from
Mycobacterium smegmatis
Authors: De Rossi Edda , Blokpoel Marian C. J. , Cantoni Rita , Branzoni Manuela , Riccardi Giovanna , Young Douglas B. , De Smet Koen A. L. , Ciferri Orio 
Published: October 2018

ABSTRACT

The nucleotide sequence and mechanism of action of a tetracycline resistance gene from
Mycobacterium smegmatis
were determined. Analysis of a 2.2-kb sequence fragment showed the presence of one open reading frame, designated
tet
(V), encoding a 419-amino-acid protein (molecular weight, 44,610) with at least 10 transmembrane domains. A database search showed that the gene is homologous to membrane-associated antibiotic efflux pump proteins but not to any known tetracycline efflux pumps. The steady-state accumulation level of tetracycline by
M. smegmatis
harboring a plasmid carrying the
tet
(V) gene was about fourfold lower than that of the parental strain. Furthermore, the energy uncoupler carbonyl cyanide
m
-chlorophenylhydrazone blocked tetracycline efflux in deenergized cells. These results suggest that the
tet
(V) gene codes for a drug antiporter which uses the proton motive force for the active efflux of tetracycline. By primer-specific amplification the gene appears to be restricted to
M. smegmatis
and
M. fortuitum
.
Paclitaxel Arrests Growth of Intracellular
Toxoplasma gondii
Authors: Estes Randee , Vogel Nicolas , Mack Douglas , McLeod Rima 
Published: October 2018

ABSTRACT

Addition of paclitaxel (Taxol) at a concentration of 1 μM to
Toxoplasma gondii
-infected human foreskin fibroblasts arrested parasite multiplication. Division of the
T. gondii
tachyzoite nucleus was inhibited, leading to syncytium-like parasite structures within the fibroblasts by 24 h after infection and treatment of the cultures. By 4 days after infection and treatment of the cultures with paclitaxel, this inhibition was irreversible, since the arrested intracellular form was incapable of leaving the host cell, infecting new cells, and initiating the growth of tachyzoites with normal morphology. Specifically, when paclitaxel was added to infected cells for 4 days and then removed by washing and the infected, paclitaxel-treated cells were cultured for 4 more days, there were no remaining
T. gondii
organisms with normal morphology. Syncytium-like structures in the cultures that were infected and treated with paclitaxel for 8 days were similar in appearance to those in preparations of infected paclitaxel-treated fibroblasts that had been cultured for 24 to 48 h. Pretreatment of the tachyzoites for 1 h with paclitaxel followed by the removal of the paclitaxel by repeatedly centrifuging and resuspending the parasites in fresh medium without paclitaxel and then adding fresh medium prior to culture of the parasites with fibroblasts did not prevent their invasion of fibroblasts but did affect their subsequent ability to replicate within fibroblasts. Pretreatment of the fibroblasts with paclitaxel also diminished subsequent replication of
T. gondii
in such host cells after 8 days. Thus, paclitaxel alters the ability of
T. gondii
to replicate in host cells. Inhibition of parasite microtubules by such compounds at concentrations which do not interfere with the function of host cell microtubules may be useful for development of novel medicines to treat
T. gondii
infections in the future.
Mode of Action of (1′
S
,2′
R
)-9-{[1′,2′-Bis(hydroxymethyl) cycloprop-1′-yl]methyl}guanine (A-5021) against Herpes Simplex Virus Type 1 and Type 2 and Varicella-Zoster Virus
Authors: Ono Nobukazu , Iwayama Satoshi , Suzuki Katsuya , Sekiyama Takaaki , Nakazawa Harumi , Tsuji Takashi , Okunishi Masahiko , Daikoku Tohru , Nishiyama Yukihiro 
Published: October 2018

ABSTRACT

The mode of action of (1′
S
,2′
R
)-9-{[1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) was studied. A-5021 was monophosphorylated at the 2′ site by viral thymidine kinases (TKs). The 50% inhibitory values for thymidine phosphorylation of A-5021 by HSV-1 TK and HSV-2 TK were comparable to those for penciclovir (PCV) and lower than those for acyclovir (ACV). Of these three agents, A-5021 inhibited VZV TK most efficiently. A-5021 was phosphorylated to a mono-, di-, and triphosphate in MRC-5 cells infected with HSV-1, HSV-2, and VZV. A-5021 triphosphate accumulated more than ACV triphosphate but less than PCV triphosphate in MRC-5 cells infected with HSV-1 or VZV, whereas HSV-2-infected MRC-5 cells had comparable levels of A-5021 and ACV triphosphates. The intracellular half-life of A-5021 triphosphate was considerably longer than that of ACV triphosphate and shorter than that of PCV triphosphate. A-5021 triphosphate competitively inhibited HSV DNA polymerases with respect to dGTP. Inhibition was strongest with ACV triphosphate, followed by A-5021 triphosphate and then (
R
,
S
)-PCV triphosphate. A DNA chain elongation experiment revealed that A-5021 triphosphate was incorporated into DNA instead of dGTP and terminated elongation, although limited chain extension was observed. Thus, the strong antiviral activity of A-5021 appears to depend on a more rapid and stable accumulation of its triphosphate in infected cells than that of ACV and on stronger inhibition of viral DNA polymerase by its triphosphate than that of PCV.
Antimicrobial Resistance of Clinical Strains of
Campylobacter jejuni
subsp.
jejuni
Isolated from 1985 to 1997 in Quebec, Canada
Authors: Gaudreau Christiane , Gilbert Huguette 
Published: October 2018

ABSTRACT

The antimicrobial resistance of 158
Campylobacter jejuni
strains isolated from humans in Quebec, Canada, from 1995 to 1997 was compared to the resistance of 47 and 86 strains of
C. jejuni
isolated in 1985 and 1986 and in 1992 and 1993, respectively. Of the 291
C. jejuni
strains tested, no strain was resistant to erythromycin. Compared to the
C. jejuni
strains isolated in 1985 and 1986, the
C. jejuni
strains isolated in 1992 and 1993 were more resistant to tetracycline (40.7 versus 19.1%, respectively;
P
= 0.01) but not to nalidixic acid or ciprofloxacin (
P
> 0.05). Compared to the
C. jejuni
strains isolated in 1992 and 1993 and in 1985 and 1986, the
C. jejuni
strains isolated from 1995 to 1997 were more resistant to tetracycline (55.7% versus 40.7 and 19.1%, respectively;
P
= 0.03 and
P
< 0.001, respectively) to nalidixic acid (13.9% versus 4.7 and 0%, respectively;
P
= 0.02 and
P
= 0.007, respectively), and to ciprofloxacin (12.7% versus 3.5 and 0%, respectively;
P
= 0.02 and
P
= 0.009, respectively).
Long-Term Therapy with the Guanine Nucleoside Analog Penciclovir Controls Chronic Duck Hepatitis B Virus Infection In Vivo
Authors: Lin Enjarn , Luscombe Carolyn , Colledge Danni , Wang Yan Yan , Locarnini Stephen 
Published: October 2018

ABSTRACT
Ducks congenitally infected with duck hepatitis B virus (DHBV) were treated with the antiviral guanine nucleoside analog penciclovir for 12 or 24 weeks at a dosage of 10 mg/kg of body weight per day. By the completion of both 12 and 24 weeks of therapy, molecular hybridization studies of the liver tissue revealed that the viral DNA, RNA, and protein levels were significantly reduced compared to those in the placebo-treated controls. Penciclovir treatment for 12 or 24 weeks was not associated with any toxicity, establishing the efficacy and safety of long-term penciclovir therapy in chronic DHBV infection.
Association of a Thr-371 Substitution in a Conserved Amino Acid Motif of Penicillin-Binding Protein 1A with Penicillin Resistance of
Streptococcus pneumoniae
Authors: Asahi Yasuko , Ubukata Kimiko 
Published: October 2018

ABSTRACT

We determined the nucleotide sequence between 1,903 and 3,097 bp of
pbp1a
, which encodes the transpeptidase domain of PBP 1A, from clinical isolates of penicillin-resistant
Streptococcus pneumoniae
(PRSP) serotypes 19 (
n
= 8), 6 (
n
= 9), 23 (
n
= 6), and 14 (
n
= 2) and two penicillin-susceptible
S. pneumoniae
(PSSP) isolates. These serotyped PRSP strains were isolated predominantly in Japan from 1993 through 1997. The 25 resistant strains were classified into five groups on the basis of the extent of sequence differences. Strains in groups I (
n
= 5; serotype 6), II (
n
= 3; serotype 19), and III (
n
= 12; different serotypes) had sequences highly homologous to the sequence of
pbp1a
of PRSP strains from South Africa, Spain, and the United States. The group IV strain (
n
= 1; serotype 14) had unique deletions from or insertions in the sequences. The sequences of group V strains (
n
= 4; serotypes 6 and 23) had relatively few differences from the sequences of the PSSP strains. For strains (
n
= 18) for which the threonine at codon 371 (Thr-371) in a conserved STMK motif of PBP 1A was substituted with an alanine or a serine (in addition to having altered
pbp2x
and
pbp2b
genes), penicillin MICs were ≧1.0 μg/ml. The PBPs 1A of these strains showed decreased affinities for [
3
H]benzylpenicillin and slightly faster mobilities on sodium dodecyl sulfate-polyacrylamide gels. In contrast, for strains (
n
= 4) without a substitution at Thr-371 in PBP 1A but with mutations in both
pbp2x
and
pbp2b
, penicillin MICs were 0.125 to 0.25 μg/ml, and the affinities of their PBPs 1A were similar to that of PSSP PBPs 1A. Furthermore, for the Thr-371-substituted strains (
n
= 3) with altered
pbp2x
genes but native
pbp2b
genes, penicillin MICs were 0.125 to 0.25 μg/ml. These results suggest that amino acid substitution of Thr-371 contributes to the development of penicillin resistance in PRSP strains with altered
pbp2x
and
pbp2b
genes.
Sordarins: A New Class of Antifungals with Selective Inhibition of the Protein Synthesis Elongation Cycle in Yeasts
Authors: Domínguez Juan Manuel , Kelly Valerie A. , Kinsman Oonagh S. , Marriott Michael S. , Gómez de las Heras Federico , Martín J. Julio 
Published: October 2018

ABSTRACT

GR135402, a sordarin derivative, was isolated in an antifungal screening program. GR135402, sordarin, and derivatives of both compounds were evaluated for their ability to inhibit cell-free translational systems from five different pathogenic fungi (
Candida albicans
,
Candida glabrata
,
Candida krusei
,
Candida parapsilosis
, and
Cryptococcus neoformans
). The activity profile of GR135402 is extended to other chemical compounds derived from sordarin. Experimental results indicate that sordarin analogs exert their antifungal effects by specifically inhibiting the protein synthesis elongation cycle in yeasts but do not affect protein synthesis machinery in mammalian systems. Intrinsically resistant strains owe their resistance to differences in the molecular target of sordarins in these strains. Preliminary studies performed to elucidate the mode of action of this new class of antifungal agents have shown that the putative target of sordarins is one of the protein synthesis elongation factors.
Rapid Ganciclovir Susceptibility Assay Using Flow Cytometry for Human Cytomegalovirus Clinical Isolates
Authors: McSharry James J. , Lurain Nell S. , Drusano George L. , Landay Alan L. , Notka Mostafa , O’Gorman Maurice R. G. , Weinberg Adriana , Shapiro Howard M. , Reichelderfer Patricia S. , Crumpacker Clyde S. 
Published: October 2018

ABSTRACT

Rapid, quantitative, and objective determination of the susceptibilities of human cytomegalovirus (HCMV) clinical isolates to ganciclovir has been assessed by an assay that uses a fluorochrome-labeled monoclonal antibody to an HCMV immediate-early antigen and flow cytometry. Analysis of the ganciclovir susceptibilities of 25 phenotypically characterized clinical isolates by flow cytometry demonstrated that the 50% inhibitory concentrations (IC
50
s) of ganciclovir for 19 of the isolates were between 1.14 and 6.66 μM, with a mean of 4.32 μM (±1.93) (sensitive; IC
50
less than 7 μM), the IC
50
s for 2 isolates were 8.48 and 9.79 μM (partially resistant), and the IC
50
s for 4 isolates were greater than 96 μM (resistant). Comparative analysis of the drug susceptibilities of these clinical isolates by the plaque reduction assay gave IC
50
s of less than 6 μM, with a mean of 2.88 μM (±1.40) for the 19 drug-sensitive isolates, IC
50
s of 6 to 8 μM for the partially resistant isolates, and IC
50
s of greater than 12 μM for the four resistant clinical isolates. Comparison of the IC
50
s for the drug-susceptible and partially resistant clinical isolates obtained by the flow cytometry assay with the IC
50
s obtained by the plaque reduction assay showed an acceptable correlation (
r
2
= 0.473;
P
= 0.001), suggesting that the flow cytometry assay could substitute for the more labor-intensive, subjective, and time-consuming plaque reduction assay.