bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacology of Novel Heteroaromatic Polycycle Antibacterials
Authors: Gross M. , Bürli R. , Jones P. , Garcia M. , Batiste B. , Kaizerman J. , Moser H. , Jiang V. , Hoch U. , Duan J.-X. , Tanaka R. , Johnson K. W. 
Published: October 2003

ABSTRACT

Heteroaromatic polycycle (HARP) compounds are a novel class of small (
M
w
, 600 to 650) DNA-binding antibacterials. HARP compounds exhibit a novel mechanism of action by preferentially binding to AT-rich sites commonly found in bacterial promoters and replication origins. Noncovalent binding in the minor groove of DNA results in inhibition of DNA replication and DNA-dependent RNA transcription and subsequent bacterial growth. HARP compounds have previously been shown to have potent in vitro activities against a broad spectrum of gram-positive organisms. The present report describes the extensive profiling of the in vitro and in vivo pharmacology of HARP antibacterials. The efficacies of representative compounds (GSQ-2287, GSQ-10547, and GSQ-11203), which exhibited good MIC activity, were tested in murine lethal peritonitis and neutropenic thigh infection models following intravenous (i.v.) administration. All compounds were efficacious in vivo, with potencies generally correlating with MICs. GSQ-10547 was the most potent compound in vitro and in vivo, with a 50% effective dose in the murine lethal peritonitis model of 7 mg/kg of body weight against methicillin-sensitive
Staphylococcus aureus
(MSSA) and 13 mg/kg against methicillin-resistant
S. aureus
(MRSA). In the neutropenic mouse thigh infection model, GSQ-11203 reduced the bacterial load (MRSA and MSSA) 2 log units following administration of a 25-mg/kg i.v. dose. In a murine lung infection model, treatment with GSQ-10547 at a dose of 50 mg/kg resulted in 100% survival. In addition to determination of efficacy in animals, the pharmacokinetic and tissue disposition profiles in animals following administration of an i.v. dose were determined. The compounds were advanced into broad safety screening studies, including screening for safety pharmacology, genotoxicity, and rodent toxicity. The results support further development of this novel class of antibiotics.
Quinine Pharmacokinetic-Pharmacodynamic Relationships in Uncomplicated Falciparum Malaria
Authors: Pukrittayakamee S. , Wanwimolruk S. , Stepniewska K. , Jantra A. , Huyakorn S. , Looareesuwan S. , White N. J. 
Published: October 2003

ABSTRACTThe relationships between the pharmacokinetic properties of quinine during a 7-day treatment course and the therapeutic response were studied in 30 adult patients with uncomplicated falciparum malaria monitored for ≥28 days. All patients received a 7-day oral quinine regimen either alone (n= 22) or in combination with rifampin (n= 8). The median fever clearance time was 58.5 h, and the mean ± standard deviation parasite clearance time was 73 ± 24 h. After recovery, six patients had recrudescences ofPlasmodium falciparummalaria and seven had delayed appearances ofP. vivaxinfection between days 16 and 23. Between the patients with and without recrudescences, there were no significant differences either in fever clearance time or parasite clearance time or in the overall pharmacokinetics of quinine and 3-hydroxyquinine. Patients for whom the area under the concentration-time curve from 3 to 7 days for quinine in plasma was <20 μg · day/ml had a relative risk of 5.3 (95% confidence interval = 1.6 to 17.7) of having a subsequent recrudescence of infection (P= 0.016). Modeling of these data suggested an average minimum parasiticidal concentration of quinine in plasma of 3.4 μg/ml and an MIC of 0.7 μg/ml for uncomplicated falciparum malaria in Thailand. To ensure a cure, the minimum parasiticidal concentration must be exceeded during four asexual cycles (>6 days).
In Vitro Activities of Garenoxacin (BMS-284756) against
Streptococcus pneumoniae
, Viridans Group Streptococci, and
Enterococcus faecalis
Compared to Those of Six Other Quinolones
Authors: Grohs Patrick , Houssaye Serge , Aubert Agnès , Gutmann Laurent , Varon Emmanuelle 
Published: October 2003

ABSTRACT

The activity of garenoxacin, a new quinolone, was determined in comparison with other quinolones against different strains of
S. pneumoniae
, viridans group streptococci (VGS), and
Enterococcus faecalis
. Strains were quinolone-susceptible clinical isolates and quinolone-resistant strains with defined mechanisms of resistance obtained from either clinical isolates or derivatives of
S. pneumoniae
R6. Clinical quinolone-susceptible strains of
S. pneumoniae
, VGS and
E. faecalis
showed garenoxacin MICs within a range of 0.03 μg/ml to 0.25 μg/ml. Garenoxacin MICs increased two- to eightfold when one mutation was present in the ParC quinolone resistance-determining region (QRDR), fourfold when one mutation was present in the GyrA QRDR (
S. pneumoniae
), 8- to 64-fold when two or three mutations were associated in ParC and GyrA QRDR, and 2,048-fold when two mutations were present in both the GyrA and ParC QRDRs (
Streptococcus pneumoniae
). Increased active efflux had a moderate effect on garenoxacin MICs for
S. pneumoniae
and VGS. Against
S. pneumoniae
, garenoxacin behaved like moxifloxacin and sparfloxacin, being more affected by a single
gyrA
mutation than by a single
parC
mutation. Although garenoxacin was generally two- to fourfold more active than moxifloxacin against the different wild-type or mutant strains of
S. pneumoniae
, VGS, and
E. faecalis
, it was two- to fourfold less active than gemifloxacin. At four times the respective MIC for each strain, the bactericidal effect of garenoxacin, observed at 6 h for
S. pneumoniae
and at 24 h for
S. oralis
and
E. faecalis
, was not influenced by the presence of mutation either in the ParC or in both the ParC and GyrA QRDRs.
Analysis of Daptomycin Efficacy and Breakpoint Standards in a Murine Model ofEnterococcus faecalisandEnterococcus faeciumRenal Infection
Authors: Alder Jeff , Li Tongchaun , Yu Donghui , Morton Larry , Silverman Jared , Zhang Xi-Xian , Critchley Ian , Thorne Grace 
Published: October 2003

ABSTRACTDaptomycin efficacy against clinical isolates ofEnterococcus faecalis,Enterococcus faecium, and a lab-derived daptomycin-resistant isolate ofE. faecaliswas investigated in a mouse model of renal infection. The daptomycin MICs against these enterococci ranged from 0.5 to 50 μg/ml. The objective of this study was to determine the relationship between the MICs of drugs againstE. faecalisandE. faeciumand the level of daptomycin exposure needed to evaluate the drug's efficacy. Correlating the required therapeutic exposures of mice with the exposures achieved clinically allowed us to project enterococcal breakpoint values. Mice pretreated with carrageenan were infected intravenously with 3 × 108to 4 × 108CFU ofE. faecalisorE. faecium. Daptomycin (5 to 50 mg of drug/kg of body weight) or saline control was administered 4 h postinfection and continued once daily for 2 days (three total doses). On day 4, infected kidneys were harvested, homogenized, and dilution plated. Efficacy was defined as a ≥2-log10(99%) reduction in bacterial burden in infected kidneys. At clinically relevant dosages and exposures (area under the curve, 400 to 600 μg · hr/ml), daptomycin demonstrated similar and marked efficacy against all clinical enterococcal isolates tested. Daptomycin achieved efficacy with comparable doses against both vancomycin-sensitive (MIC, ≤4 μg/ml) and -resistant enterococcal strains tested. Efficacy was also established against the lab-derived daptomycin-resistantE. faecalisisolate. In this murine renal infection model, clinically relevant exposures of daptomycin were effective againstE. faecalisandE. faeciumstrains for which MICs were ≤8 μg/ml. These murine efficacy data for daptomycin, along with surveillance data and human pharmacokinetic exposures achieved, suggest a breakpoint concentration value of ≤8 μg/ml (susceptible) and ≥16 μg/ml (resistant) for daptomycin againstE. faeciumandE. faecalis.
In Vitro Activity of TD-6424 againstStaphylococcus aureus
Authors: Pace John L. , Krause Kevin , Johnston Deborah , Debabov Dmitri , Wu Terry , Farrington Lesley , Lane Cassie , Higgins Deborah L. , Christensen Burt , Judice J. Kevin , Kaniga Koné 
Published: October 2003

ABSTRACTTD-6424, a rapidly bactericidal agent with multiple mechanisms of action, is more potent in vitro and more rapidly bactericidal than currently available agents against methicillin-susceptible and methicillin-resistantStaphylococcus aureus. TD-6424 produces a postantibiotic effect with a duration of 4 to 6 h against these organisms. The results suggest potential efficacy against susceptible and resistant strains ofS. aureus.
First
Streptococcus agalactiae
Isolates Highly Resistant to Quinolones, with Point Mutations in
gyrA
and
parC
Authors: Kawamura Yoshiaki , Fujiwara Hiromitsu , Mishima Noriko , Tanaka Yuko , Tanimoto Ayako , Ikawa Shiro , Itoh Youko , Ezaki Takayuki 
Published: October 2003

ABSTRACT

Three isolates of
Streptococcus agalactiae
highly resistant to multiple fluoroquinolones were isolated in Japan. Compared with susceptible strains of
S. agalactiae
, these quinolone-resistant strains had double point mutations within the quinolone resistance-determining regions of
gyrA
and
parC
; Ser-81 was changed to Leu (TCA → TTA) in the amino acid sequence deduced from
gyrA
, and Ser-79 was changed to Phe (TCC → TTC) in the amino acid sequence deduced from
parC
. Comparative sequence analysis revealed the possibility of gene transfer between
S. agalactiae
and another beta-hemolytic streptococcus,
Streptococcus difficile
.
Inhibition of the Complement Membrane Attack Complex bySchistosoma mansoniParamyosin
Authors: Deng Jiusheng , Gold Daniel , LoVerde Philip T. , Fishelson Zvi 
Published: October 2003

ABSTRACTLarvae and adults of the parasitic blood flukeSchistosoma mansoniare resistant to killing by human complement. An earlier search by Parizade et al. for a schistosome complement inhibitor identified a 94-kDa surface protein which was named SCIP-1 (M. Parizade, R. Arnon, P. J. Lachmann, and Z. Fishelson, J. Exp. Med. 179:1625-1636, 1994). Following partial purification and analysis by mass spectrometry, we have determined SCIP-1 to be a surface-exposed form of the muscle protein paramyosin. As shown by immunofluorescence, anti-paramyosin antibodies label the surface of live schistosomula and adult worms. Like SCIP-1, purified native paramyosin reacts with a polyclonal rabbit anti-human CD59 antiserum, as shown by Western blot analysis. Also, the human complement components C8 and C9 bind to recombinant and native paramyosin. Analysis of paramyosin binding to fragments of C9 generated by thrombin or trypsin has demonstrated that paramyosin binds to C9 at a position located between Gly245 and Arg391. Paramyosin inhibited Zn2+-induced C9 polymerization and poly-C9 deposition onto rabbit erythrocytes (ER). In addition, paramyosin inhibited lysis of ERand of sensitized sheep erythrocytes by human complement. Finally, anti-paramyosin antibodies enhanced in vitro killing of schistosomula by normal and C4-depleted human complement. Taken together, these findings suggest that an exogenous form ofS. mansoniparamyosin inhibits activation of the terminal pathway of complement and thus has an important immunomodulatory role in schistosomiasis.
Type 1 Fimbriae ofSalmonella entericaSerovar Typhimurium Bind to Enterocytes and Contribute to Colonization of Swine In Vivo
Authors: Althouse Carrie , Patterson Sheila , Fedorka-Cray Paula , Isaacson Richard E. 
Published: October 2003

ABSTRACTSalmonella entericaserovar Typhimurium strain 798 is a clinical isolate from a pig and is known to be able to cause persistent, asymptomatic infections. This strain also is known to exist in two phenotypes (adhesive and nonadhesive to enterocytes) and can switch between the two phenotypes at a rate consistent with phase variation. Cells in the adhesive phenotype are more readily phagocytosed by leukocytes than nonadhesive cells. Once in a leukocyte, adhesive-phase cells survive while nonadhesive-phase cells die. In the present study, nonadhesive mutants were obtained with the transposon TnphoA. A nonadhesive mutant was selected for study and was shown by electron microscopy not to produce fimbriae. The gene encoding the adhesin was cloned and sequenced. Based on its sequence, the adhesin was shown to be FimA, the major subunit of type 1 fimbriae. The nonadhesive mutant was attenuated in its ability to colonize both mouse and pig intestines, but remained capable of systemic spread in mice. The nonadhesive mutant was phagocytosed to the same extent as parental cells in the adhesive phase and then survived intracellularly. These results demonstrated that type 1 fimbriae were important for attachment to enterocytes and promoted intestinal colonization. However, they were not important in promoting phagocytosis or intracellular survival.
Growth Phase-Dependent Response ofHelicobacter pylorito Iron Starvation
Authors: Merrell D. Scott , Thompson Lucinda J. , Kim Charles C. , Mitchell Hazel , Tompkins Lucy S. , Lee Adrian , Falkow Stanley 
Published: October 2003

ABSTRACTIron is an essential nutrient that is often found in extremely limited available quantities within eukaryotic hosts. Because of this, many pathogenic bacteria have developed regulated networks of genes important for iron uptake and storage. In addition, it has been shown that many bacteria use available iron concentrations as a signal to regulate virulence gene expression. We have utilized DNA microarray technology to identify genes of the human pathogenHelicobacter pylorithat are differentially regulated on a growth-inhibiting shift to iron starvation conditions. In addition, the growth phase-dependent expression of these genes was investigated by examining both exponential and stationary growth phase cultures. We identified known iron-regulated genes, as well as a number of genes whose regulation by iron concentration was not previously appreciated. Included in the list of regulated factors were the known virulence genescagA,vacA, andnapA. We examined the effect of iron starvation on the motility ofH. pyloriand found that exponential- and stationary-phase cultures responded differently to the stress. We further found that while growing cells are rapidly killed by iron starvation, stationary-phase cells show a remarkable ability to survive iron depletion. Finally, bioinformatic analysis of the predicted promoter regions of the differentially regulated genes led to identification of several putative Fur boxes, suggesting a direct role for Fur in iron-dependent regulation of these genes.
Simultaneous Variation of the Immunodominant Outer Membrane Proteins, MSP2 and MSP3, duringAnaplasma marginalePersistence In Vivo
Authors: Brayton Kelly A. , Meeus Patrick F. M. , Barbet Anthony F. , Palmer Guy H. 
Published: October 2003

ABSTRACTVector-borne bacterial pathogens persist in the mammalian host by varying surface antigens to evade the existing immune response. To test whether the model of surface coat switching and immune evasion can be extended to a vector-borne bacterial pathogen with multiple immunodominant surface proteins, we examinedAnaplasma marginale, a rickettsia with two highly immunogenic outer membrane proteins, major surface protein 2 (MSP2) and MSP3. The simultaneous clearance of variants of the two most immunodominant surface proteins ofA.marginalefollowed by emergence of unique variants indicates that the switch rates and immune selection for MSP2 and MSP3 are sufficiently similar to explain the cyclic bacteremia observed during infection in the immunocompetent host.
Evaluation of Medium-Dose UVA1 Phototherapy in Localized Scleroderma with the Cutometer and Fast Fourier Transform Method
Authors: de Rie M.A. , Enomoto D.N.H. , de Vries H.J.C. , Bos J.D. 
Published: October 2003

<i>Purpose:</i> To evaluate the efficacy of medium-dose UVA1 phototherapy in patients with localized scleroderma. <i>Method:</i> A controlled pilot study with medium-dose UVA1 (48 J/cm<sup>2</sup>) was performed. The results were evaluated by means of a skin score and two objective methods for quantifying sclerosis (cutometer and fast Fourier transform method). Patients were treated 4 times a week for 5 weeks. The follow-up period was 12 weeks. <i>Results:</i> All patients responded to therapy. Skin score and cutometer results showed improvement of skin elasticity of treated skin compared to control skin. Fast Fourier transform measurements showed no change in bundle orientation ratio and spacing. <i>Conclusion:</i> We concluded that treatment for 12 weeks 4 times a week with medium-dose UVA1 may be a beneficial therapy and a well-tolerated treatment modality for localized scleroderma (morphea). After 12 weeks, improvement of skin sclerosis can be detected by skin score and cutometer measurements but not by the fast Fourier transform method.
Reappraisal of the human vestibular cortex by cortical electrical stimulation study
Authors: Kahane Philippe , Hoffmann Dominique , Minotti Lorella , Berthoz Alain 
Published: October 2003

AbstractThe cortical areas with vestibular input in humans were assessed by electrical stimulation in 260 patients with partial epilepsy who had undergone stereotactic intracerebral electroencephalogram recordings before surgery. Vestibular symptoms were electrically induced on 44 anatomical sites in 28 patients. The patients experienced illusions of rotation (yaw plane: 18, pitch plane: 6, roll plane: 6), translations (n = 6), or indefinable feelings of body motion (n = 8). Almost all vestibular sites were located in the cortex (41/44): in the temporal (n = 19), parietal (n = 14), frontal (n = 5), occipital (n = 2), and insular (n = 1) lobes. Among these sites, we identified a lateral cortical temporoparietal area we called the temporo–peri‐Sylvian vestibular cortex (TPSVC), from which vestibular symptoms, and above all rotatory sensations, were particularly easily elicited (24/41 cortical sites, 58.5%). This area extended above and below the Sylvian fissure, mainly inside Brodmann areas 40, 21, and 22. It included the parietal operculum (9/24 TPSVC sites) which was particularly sensitive for eliciting pitch plane illusions, and the mid and posterior part of the first and second temporal gyri (15/24 TPSVC sites) which preferentially caused yaw plane illusions. We suggest that the TPSVC could be homologous with the monkey's parietoinsular vestibular cortex.
Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy
Authors: Herzog Andrew G. , Coleman Anton E. , Jacobs Alan R. , Klein Pavel , Friedman Mark N. , Drislane Frank W. , Ransil Bernard J. , Schomer Donald L. 
Published: October 2003

AbstractWe evaluated reproductive endocrine function in women with unilateral temporolimbic epilepsy and normal control subjects to assess the effects of epilepsy, epilepsy laterality, and antiepileptic drug use on the cerebral regulation of hormonal secretion. The findings indicate that reproductive endocrine function differs between women with epilepsy and normal control subjects. Significant differences exist at all levels of the reproductive neuroendocrine axis, that is, hypothalamus, pituitary, and peripheral gland. Differences show significant relationships to the epilepsy itself as well as to medication use. Reproductive neuroendocrine changes occur in a stochastic manner such that the laterality of unilateral temporolimbic discharges is associated with predictable directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis. These directional changes are consistent with the finding that different reproductive disorders may develop in relation to left‐ and right‐sided temporolimbic epilepsy. Hormonal changes can show close temporal relationship to the occurrence of interictal epileptiform discharges and may vary in relation to the laterality of the discharges. Antiepileptic drugs differ in their effects on reproductive hormone levels. There are notable differences between enzyme‐inducing and noninducing drugs. Menstrual disorders are more common among women with interictal discharges as well as women with abnormal hormonal findings. Ann Neurol 2003;54:625–637
Embryo/fetal development studies with hydroxypropyl methylcellulose acetate succinate (HPMCAS) in rats and rabbits
Authors: Cappon Gregg D. , Fleeman Tammye L. , Rocca Meredith S. , Cook Jon C. , Hurtt Mark E. 
Published: October 2003

AbstractBACKGROUND: Hoshi et al. [Hoshi et al. J Toxicol Sci 10(Suppl):187–255, 1985a,b,c,d] evaluated the potential for hydroxypropyl methylcellulose acetate succinate (HPMCAS) to produce developmental and reproductive toxicity in a series of studies that included rat and rabbit teratology studies, a rat fertility study, and a rat peri‐ and postnatal study. The authors concluded that there were no compound‐related findings. In the cesarean‐section phase of the rat teratology study, however, clubfoot was reported for 0.8, 2.1, 5.5, and 4.1% of fetuses in the control, 625, 1250, and 2500 mg/kg groups, respectively. There were no significant increases in external anomalies, but the apparent dose‐related increase in clubfoot was not specifically addressed. In the rabbit teratology study, the number of litters evaluated (12–13 per group) was not consistent with current regulatory guidelines. Therefore, to definitively establish the potential of HPMCAS to produce developmental toxicity, embryo/fetal development studies were carried out in rats and rabbits. METHODS: Groups of 20 pregnant Sprague–Dawley rats and New Zealand White rabbits were dosed with 0, 50, 150, 625, or 2500 mg/kg HPMCAS from gestational day (GD) 6–17 or GD 7–19 for rats and rabbits, respectively. Fetuses were collected by cesarean section and examined for external, visceral and skeletal development. RESULTS: No developmental toxicity was observed as a result of HPMCAS exposure demonstrating that maternal HPMCAS exposure during gestation does not induce developmental anomalies. There were no findings of clubfoot or other limb anomalies in these studies at dose levels equivalent to those that were previously associated with a possible increase in clubfoot. CONCLUSIONS: The conclusion of the earlier study indicating that treatment with HPMCAS at doses up to and including 2500 mg/kg did not produce developmental toxicity was confirmed with these studies. It is likely that the clubfoot noted in the earlier rat teratology study was a misdiagnosis or artifact. Birth Defects Res B 68:421–427, 2003. © 2003 Wiley‐Liss, Inc.