bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tolevamer Is Not Efficacious in the Neutralization of Cytotoxin in a Human Gut Model of
Clostridium difficile
Infection
Authors: Baines Simon D. , Freeman Jane , Wilcox Mark H. 
Published: February 2009

ABSTRACT

The efficacy of tolevamer, a nonantimicrobial styrene derivative toxin-binding agent, in treating simulated
Clostridium difficile
infection in an in vitro human gut model was investigated. Tolevamer reduced neither the duration nor magnitude of cytotoxin activity by
C. difficile
, reflecting poor efficacy observed in recent phase III clinical trials.
Contribution of Oxidative Damage to Antimicrobial Lethality
Authors: Wang Xiuhong , Zhao Xilin 
Published: February 2009

ABSTRACT

A potential pathway linking hydroxyl radicals to antimicrobial lethality was examined by using mutational and chemical perturbations of
Escherichia coli
. Deficiencies of
sodA
or
sodB
had no effect on norfloxacin lethality; however, the absence of both genes together reduced lethal activity, consistent with rapid conversion of excessive superoxide to hydrogen peroxide contributing to quinolone lethality. Norfloxacin was more lethal with a mutant deficient in
katG
than with its isogenic parent, suggesting that detoxification of peroxide to water normally reduces quinolone lethality. An iron chelator (bipyridyl) and a hydroxyl radical scavenger (thiourea) reduced the lethal activity of norfloxacin, indicating that norfloxacin-stimulated accumulation of peroxide affects lethal activity via hydroxyl radicals generated through the Fenton reaction. Ampicillin and kanamycin, antibacterials unrelated to fluoroquinolones, displayed behavior similar to that of norfloxacin except that these two agents showed hyperlethality with an
ahpC
(alkyl hydroperoxide reductase) mutant rather than with a
katG
mutant. Collectively, these data are consistent with antimicrobial stress increasing the production of superoxide, which then undergoes dismutation to peroxide, from which a highly toxic hydroxyl radical is generated. Hydroxyl radicals then enhance antimicrobial lethality, as suggested by earlier work. Such findings indicate that oxidative stress networks may provide targets for antimicrobial potentiation.
Model-Based Approach To Characterize Efavirenz Autoinduction and Concurrent Enzyme Induction with Carbamazepine
Authors: Zhu Min , Kaul Sanjeev , Nandy Partha , Grasela Dennis M. , Pfister Marc 
Published: February 2009

ABSTRACTCharacterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.
Lack of a Clinically Important Effect of Moderate Hepatic Insufficiency and Severe Renal Insufficiency on Raltegravir Pharmacokinetics
Authors: Iwamoto Marian , Hanley William D. , Petry Amelia S. , Friedman Evan J. , Kost James T. , Breidinger Sheila A. , Lasseter Kenneth C. , Robson Richard , Lunde Norman M. , Wenning Larissa A. , Stone Julie A. , Wagner John A. 
Published: February 2009

ABSTRACTRaltegravir is a human immunodeficiency virus type 1 integrase strand transfer inhibitor with potent activity in vitro and in vivo. Raltegravir is primarily cleared by hepatic metabolism via glucuronidation (via UDP glucuronosyltransferase 1A1), with a minor component of elimination occurring via the renal pathway. Since the potential exists for raltegravir to be administered to patients with hepatic or renal insufficiency, two studies were conducted to evaluate the influence of moderate hepatic insufficiency (assessed by using the Child-Pugh criteria) and severe renal insufficiency (creatinine clearance, <30 ml/min/1.73 m2) on the pharmacokinetics of raltegravir. Study I evaluated the pharmacokinetics of 400 mg raltegravir in eight patients with moderate hepatic insufficiency and eight healthy, matched control subjects. Study II evaluated the pharmacokinetics of 400 mg raltegravir in 10 patients with severe renal insufficiency and 10 healthy, matched control subjects. All participants received a single 400-mg dose of raltegravir in the fasted state. In study I, the geometric mean ratios (GMR; mean value for the group with moderate hepatic insufficiency/mean value for the healthy controls) and 90% confidence intervals (CIs) for the area under the concentration-time curve from time zero to infinity (AUC0-∞), the maximum concentration of drug in plasma (Cmax), and the concentration at 12 h (C12) were 0.86 (90% CI, 0.41, 1.77), 0.63 (90% CI, 0.23, 1.70), and 1.26 (90% CI, 0.65, 2.43), respectively. In study II, the GMRs (mean value for the group with renal insufficiency/mean value for the healthy controls) and 90% CIs for AUC0-∞,Cmax, andC12were 0.85 (90% CI, 0.49, 1.49), 0.68 (90% CI, 0.35, 1.32), and 1.28 (90% CI, 0.79, 2.06), respectively. Raltegravir was generally well tolerated by patients with moderate hepatic or severe renal insufficiency, and there was no clinically important effect of moderate hepatic or severe renal insufficiency on the pharmacokinetics of raltegravir. No adjustment in the dose of raltegravir is required for patients with mild or moderate hepatic or renal insufficiency.
Pharmacokinetics of LB80331 and LB80317 following Oral Administration of LB80380, a New Antiviral Agent for Chronic Hepatitis B (CHB), in Healthy Adult Subjects, CHB Patients, and Mice
Authors: Yuen Man-Fung , Lee Sung-Hack , Kang Hyang-Mi , Kim Chung Ryeol , Kim John , Ngai Vincent , Lai Ching-Lung 
Published: February 2009

ABSTRACTLB80380, a dipivoxil ester prodrug of LB80331 (metabolite, LB80317), is a novel antiviral agent for chronic hepatitis B (CHB). The pharmacokinetics of LB80331/LB80317 were evaluated in two clinical studies and a study with mice. The clinical studies were dose-escalating pharmacokinetic studies with six healthy subjects per single-dose group and six CHB patients per repeated-dose group. The mouse study was designed to measure the amounts of the phosphorylated portions of LB80331 and LB80317 in the liver. In healthy subjects receiving a single dose of LB80380, the plasma level of LB80331 increased as the dose increased. Although a high-fat diet delayed the time to the maximum concentration in plasma (Tmax) of LB80331, the area under the concentration-time curve from time zero to infinity was similar between the subjects in the fasted group and those in the group who consumed a high-fat diet. In CHB patients, the meanTmaxof LB80331 was 1.0 to 2.0 h postdosing at steady state. The steady-state plasma concentration of LB80331 declined in a monoexponential manner, and the apparent elimination half-life was 2.5 to 3.3 h. The steady-state plasma concentration of LB80317 was maximum at 3 to 8 h postdoing and declined in a monoexponential manner; the apparent elimination half-life was 45 to 62 h at the 30- to 240-mg doses, while LB80317 was measurable in plasma only at higher doses of 120 and 240 mg after the administration of the first dose of LB80380. Forty percent of the amount of LB80331/LB80317 in the mouse liver was detected as the phosphorylated form. In conclusion, LB80380 is rapidly absorbed and converted to LB80331. LB80317 has a long half-life at steady-state, supporting the use of a once-daily dosing regimen. The ingestion of a high-fat diet delays the rate of absorption of LB80380 without affecting the extent of absorption.
Novel Imino Sugar Derivatives Demonstrate Potent Antiviral Activity against Flaviviruses
Authors: Chang Jinhong , Wang Lijuan , Ma Dongling , Qu Xiaowang , Guo Haitao , Xu Xiaodong , Mason Peter M. , Bourne Nigel , Moriarty Robert , Gu Baohua , Guo Ju-Tao , Block Timothy M. 
Published: February 2009

ABSTRACT

Imino sugars, such as
N
-butyl-deoxynojirimycin and
N
-nonyl-deoxynojirimycin (NNDNJ), are glucose analogues that selectively inhibit cellular α-glucosidase I and II in the endoplasmic reticulum and exhibit antiviral activities against many types of enveloped viruses. Although these molecules have broad-spectrum antiviral activity, their development has been limited by a lack of efficacy and/or selectivity. We have previously reported that a DNJ derivative with a hydroxylated cyclohexyl side chain, called OSL-95II, has an antiviral efficacy similar to that of NNDNJ but significantly less toxicity. Building upon this observation, a family of imino sugar derivatives containing an oxygenated side chain and terminally restricted ring structures were synthesized and shown to have low cytotoxicity and superior antiviral activity against members of the
Flaviviridae
family, including bovine viral diarrhea virus, dengue virus (DENV), and West Nile virus. Of particular interest is that several of these novel imino sugar derivatives, such as PBDNJ0801, PBDNJ0803, and PBDNJ0804, potently inhibit DENV infection in vitro, with 90% effective concentration values at submicromolar concentrations and selectivity indices greater than 800. Therefore, these compounds represent the best in their class and may offer realistic candidates for the development of antiviral therapeutics against human DENV infections.
Effects of Double and Triple Combinations of Antifungal Drugs in a Murine Model of Disseminated Infection by
Scedosporium prolificans
Authors: Rodríguez M. Mar , Calvo Enrique , Serena Carolina , Mariné Marçal , Pastor F. Javier , Guarro Josep 
Published: February 2009

ABSTRACT

We have evaluated the efficacies of micafungin, amphotericin B, and voriconazole, alone and in double and triple combinations, in a murine model of systemic infection by
Scedosporium prolificans
. Micafungin combined with voriconazole or amphotericin B was the most effective, these being the only treatments able to prolong survival and to reduce the fungal load in the kidneys and brain. Triple combinations of these drugs did not improve the results obtained with double combinations.
Single-Dose Escalation and Multiple-Dose Safety, Tolerability, and Pharmacokinetics of IDX899, a Candidate Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor, in Healthy Subjects
Authors: Zhou Xiao-Jian , Pietropaolo Keith , Damphousse David , Belanger Bruce , Chen Jie , Sullivan-Bólyai John , Mayers Douglas 
Published: February 2009

ABSTRACT

IDX899 is a novel nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant strains of human immunodeficiency virus type 1 (HIV-1) and with a high genetic barrier to resistance. Single rising doses of 50 and 100 (given by use of a 50-mg capsule) and 200, 400, 800, and 1,200 mg (given by use of a 200-mg capsule) of IDX899 or matching placebo were administered sequentially to cohorts of healthy male subjects, followed by the administration of multiple doses of 800 mg once daily (QD) or 400 mg twice daily (BID) for 7 days. A single dose of 400 mg was also administered to a cohort of females. IDX899 was administered orally under fasted (50- to 400-mg doses) and then fed (≥200-mg doses) conditions. Exposure to IDX899 was dose proportional and comparable in males and females. With a different drug-to-excipient ratio, the 50-mg capsule led to a higher exposure but a shorter mean terminal half-life (
t
1/2
) of 6.2 to 6.8 h. The 200-mg capsule resulted in a more sustained exposure with a longer mean
t
1/2
of 7.9 to 14.6 h. Food enhanced absorption by approximately twofold, while it delayed the time to the maximum concentration. The mean concentration at 24 h following the administration of a single 200-mg dose under fed conditions exceeded the in vitro protein binding-adjusted 90% inhibitory concentration by fourfold. The levels of plasma exposure were similar between the single dosing and the repeat dosing with 800 mg QD and was approximately twofold higher with 400 mg BID. Mean steady-state trough levels were 0.9 μg/ml (range, 0.2 to 2.5 μg/ml) and 2.1 μg/ml (range, 0.5 to 4.5 μg/ml) for the 800-mg QD and 400-mg BID regimens, respectively. The level of excretion of unchanged drug in urine was negligible. IDX899 was well tolerated; and no serious adverse events, dose-dependent adverse events, or laboratory abnormalities were detected. These favorable safety and pharmacokinetic results support further clinical studies with patients with HIV-1 infection by the use of a QD regimen.
Antianaerobic Activity of Sulopenem Compared to Six Other Agents
Authors: Ednie Lois M. , Appelbaum Peter C. 
Published: February 2009

ABSTRACT

Agar dilution MIC methodology was used to compare the activity of sulopenem with those of amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin-tazobactam, imipenem, clindamycin, and metronidazole against 431 anaerobes. Overall, MIC
50
/
90
values were as follows: sulopenem, 0.25/1.0 μg/ml; amoxicillin/clavulanate, 0.5/2.0 μg/ml; ampicillin/sulbactam, 0.5/4.0 μg/ml; piperacillin/tazobactam, 0.25/8.0 μg/ml; imipenem, 0.06/1.0 μg/ml; clindamycin, 0.25/16.0 μg/ml; and metronidazole, 1.0/4.0 μg/ml.
Susceptibility of Human Immunodeficiency Virus Type 1 to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag Spacer Peptide 1
Authors: Van Baelen Kurt , Salzwedel Karl , Rondelez Evelien , Van Eygen Veerle , De Vos Stephanie , Verheyen Ann , Steegen Kim , Verlinden Yvan , Allaway Graham P. , Stuyver Lieven J. 
Published: February 2009

ABSTRACT

In this study, we evaluated baseline susceptibility to bevirimat (BVM), the first in a new class of antiretroviral agents, maturation inhibitors. We evaluated susceptibility to BVM by complete
gag
genotypic and phenotypic testing of 20 patient-derived human immunodeficiency virus type 1 isolates and 20 site-directed mutants. We found that reduced BVM susceptibility was associated with naturally occurring polymorphisms at positions 6, 7, and 8 in Gag spacer peptide 1.
Reduced Efficacy of Intermittent Preventive Treatment of Malaria in Malnourished Children
Authors: Danquah Ina , Dietz Ekkehart , Zanger Philipp , Reither Klaus , Ziniel Peter , Bienzle Ulrich , Mockenhaupt Frank P. 
Published: February 2009

ABSTRACT

Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on the incidence of malaria and on the protective efficacy of IPTi in a cohort of 1,200 children in northern Ghana, where malaria is hyperendemic. These children received IPTi-SP or placebo at 3, 9, and 15 months of age and were monitored until 24 months of age. Malnutrition was present in 32, 40, and 50% of children at ages 3, 9, and 15 months, respectively. It was associated with increased risks of severe anemia and death but not an increased risk of malaria. Although malaria slightly contributed to chronic malnutrition, IPTi did not substantially improve child growth. Importantly, the protective efficacies of IPTi in malnourished children were roughly half or even less of those observed in nonmalnourished children. In the first year of life, IPTi reduced the incidence of malaria to a significantly lesser extent in infants who received both doses in a malnourished condition (25%; 95% confidence interval [CI], −7 to 48%) compared to that of nonmalnourished children (46%; 95% CI, 30 to 58%;
P
= 0.049). Moreover, in contrast to nutritionally advantaged children, the rate of severe malaria appeared to be increased in malnourished children who took IPTi. IPTi might exhibit reduced efficacy in regions of abundant malnutrition. Concomitant nutrition programs may be needed in these places to achieve the desired impact.
The RNA Chaperone Hfq Is Involved in Stress Response and Virulence in
Neisseria meningitidis
and Is a Pleiotropic Regulator of Protein Expression
Authors: Fantappiè Laura , Metruccio Matteo M. E. , Seib Kate L. , Oriente Francesca , Cartocci Elena , Ferlicca Francesca , Giuliani Marzia M. , Scarlato Vincenzo , Delany Isabel 
Published: February 2009

ABSTRACT

The well-conserved protein Hfq has emerged as the key modulator of riboregulation in bacteria. This protein is thought to function as an RNA chaperone and to facilitate base pairing between small regulatory RNA (sRNA) and mRNA targets, and many sRNAs are dependent on the Hfq protein for their regulatory functions. To address the possible role of Hfq in riboregulated circuits in
Neisseria meningitidis
, we generated an Hfq mutant of the MC58 strain, and the knockout mutant has pleiotropic phenotypes; it has a general growth phenotype in vitro in culture media, and it is sensitive to a wide range of stresses, including those that it may encounter in the host. Furthermore, the expression profile of a vast number of proteins is clearly altered in the mutant, and we have identified 27 proteins by proteomics. All of the phenotypes tested to date are also restored by complementation of Hfq expression in the mutant strain. Importantly, in ex vivo and in vivo models of infection the Hfq mutant is attenuated. These data indicate that Hfq plays a key role in stress response and virulence, and we propose a major role for Hfq in regulation of gene expression. Moreover, this study suggests that in meningococcus there is a large Hfq-mediated sRNA network which so far is largely unexplored.
A Baculovirus Dual Expression System-Based Malaria Vaccine Induces Strong Protection againstPlasmodium bergheiSporozoite Challenge in Mice
Authors: Yoshida Shigeto , Kawasaki Masanori , Hariguchi Norimitsu , Hirota Kuniko , Matsumoto Makoto 
Published: February 2009

ABSTRACTWe have previously shown that a recombinant baculovirus that displaysPlasmodium bergheicircumsporozoite protein (PbCSP), a homolog of the leading human malaria vaccine candidate, on the viral envelope protected 60% of mice againstP. bergheiinfection. Here, we describe a second-generation baculovirus vaccine based on the “baculovirus dual expression system,” which drives PbCSP expression by a dual promoter that consists of tandemly arranged baculovirus-derived polyhedrin and mammal-derived cytomegalovirus promoters. The baculovirus-based PbCSP vaccine not only displayed PbCSP on the viral envelope but also expressed PbCSP upon transduction of mammalian cells. Immunization with the baculovirus-based PbCSP vaccine elicited high PbCSP-specific antibody titers (predominantly immunoglobulin G1 [IgG1] and IgG2a) and PbCSP-specific CD8+T-cell responses without extraneous immunological adjuvants in mice, indicating that there was induction of both Th1 and Th2 responses (a mixed Th1/Th2 response). Importantly, upon intramuscular inoculation, the baculovirus-based PbCSP vaccine conferred complete protection against sporozoite challenge. Thus, the baculovirus-based PbCSP vaccine induced strong protective immune responses against preerythrocytic parasites. These results introduce a novel concept for the baculovirus dual expression system that functions as both a subunit vaccine and a DNA vaccine and offer a promising new alternative to current human vaccine delivery platforms.
Analysis of Immunity to Febrile Malaria in Children That Distinguishes Immunity from Lack of Exposure
Authors: Bejon Philip , Warimwe George , Mackintosh Claire L. , Mackinnon Margaret J. , Kinyanjui Sam M. , Musyoki Jennifer N. , Bull Peter C. , Marsh Kevin 
Published: February 2009

ABSTRACT
In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of “protection.” However, apparent “protection” may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than “immune.” Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.
Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes
Authors: Negri Donatella R. M. , Pinto Dora , Vendetti Silvia , Patrizio Mario , Sanchez Massimo , Riccomi Antonella , Ruggiero Paolo , Del Giudice Giuseppe , De Magistris Maria Teresa 
Published: February 2009

ABSTRACTB lymphocytes play an important role in the immune response induced by mucosal adjuvants. In this study we investigated the in vitro antigen-presenting cell (APC) properties of human B cells upon treatment with cholera toxin (CT) andEscherichia coliheat-labile enterotoxin (LT) and nontoxic counterparts of these toxins, such as the B subunit of CT (CT-B) and the mutant of LT lacking ADP ribosyltransferase activity (LTK63). Furthermore, forskolin (FSK), a direct activator of adenylate cyclase, and cyclic AMP (cAMP) analogues were used to investigate the role of the increase in intracellular cAMP caused by the A subunit of CT and LT. B lymphocytes were cultured with adjuvants and polyclonal stimuli necessary for activation of B cells in the absence of CD4 T cells. Data indicated that treatment with CT, LT, FSK, or cAMP analogues, but not treatment with CT-B or LTK63, upregulated surface activation markers on B cells, such as CD86 and HLA-DR, and induced inhibition of the proliferation of B cells at early time points, while it increased cell death in long-term cultures. Importantly, B cells treated with CT, LT, or FSK were able to induce pronounced proliferation of both CD4+and CD8+allogeneic T cells compared with untreated B cells and B cells treated with CT-B and LTK63. Finally, only treatment with toxins or FSK induced antigen-specific T-cell proliferation inMycobacterium tuberculosispurified protein derivative or tetanus toxoid responder donors. Taken together, these results indicated that the in vitro effects of CT and LT on human B cells are mediated by cAMP.