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  • American Society for Microbiology  (13)
  • Pharmacy  (13)
  • 1
    Online Resource
    Online Resource
    Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae
    American Society for Microbiology ; 2016
    In:  Antimicrobial Agents and Chemotherapy Vol. 60, No. 12 ( 2016-12), p. 7347-7356
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 60, No. 12 ( 2016-12), p. 7347-7356
    Abstract: Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish ( Danio rerio ) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor β (TGF-β). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01693-16
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2016
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  • 2
    Online Resource
    Online Resource
    In Vitro Activities of Iboga Alkaloid Congeners Coronaridine and 18-Methoxycoronaridine against Leishmania amazonensis
    American Society for Microbiology ; 2002
    In:  Antimicrobial Agents and Chemotherapy Vol. 46, No. 7 ( 2002-07), p. 2111-2115
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 46, No. 7 ( 2002-07), p. 2111-2115
    Abstract: In previous studies, we demonstrated the leishmanicide effect of coronaridine, a natural indole alkaloid isolated from stem bark of Peschiera australis (Delorenzi et al., Antimicrob. Agents Chemother. 45: 1349-1354, 2001). In this study we show the leishmanicidal effect of the synthetic coronaridine and its racemic 18-methoxylated analog, 18-methoxycoronaridine. Both alkaloids revealed a potent leishmanicide effect against Leishmania amazonensis , a causative agent of cutaneous and diffuse cutaneous leishmaniasis in the New World. Despite their potent leishmanicide effect, both alkaloids were neither toxic to murine macrophages nor did they modulate their oxidative or cytokine production responses.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.46.7.2111-2115.2002
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2002
    detail.hit.zdb_id: 1496156-8
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  • 3
    Online Resource
    Online Resource
    Antistaphylococcal Activities of the New Fluoroquinolone JNJ-Q2
    American Society for Microbiology ; 2011
    In:  Antimicrobial Agents and Chemotherapy Vol. 55, No. 12 ( 2011-12), p. 5512-5521
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 55, No. 12 ( 2011-12), p. 5512-5521
    Abstract: The new broad-spectrum fluoroquinolone JNJ-Q2 displays in vitro activity against Gram-negative and Gram-positive organisms, including methicillin-resistant Staphylococcus aureus (MRSA) and ciprofloxacin-resistant MRSA isolates. Tested with isogenic methicillin-susceptible S. aureus (MSSA) and MRSA strains bearing quinolone-resistant target mutations, JNJ-Q2 displayed MICs ≤ 0.12 μg/ml, values 16- to 32-fold lower than those determined for moxifloxacin. Overexpression of the NorA efflux pump did not impact JNJ-Q2 MICs. Inhibition of S. aureus DNA gyrase and DNA topoisomerase IV enzymes demonstrated that JNJ-Q2 was more potent than comparators against wild-type enzymes and enzymes carrying quinolone-resistant amino acid substitutions, and JNJ-Q2 displayed equipotent activity against both enzymes. In serial-passage studies comparing resistance selection in parallel MRSA cultures by ciprofloxacin and JNJ-Q2, ciprofloxacin readily selected for mutants displaying MIC values of 128 to 512 μg/ml, which were observed within 18 to 24 days of passage. In contrast, cultures passaged in the presence of JNJ-Q2 displayed MICs ≤ 1 μg/ml for a minimum of 27 days of serial passage. A mutant displaying a JNJ-Q2 MIC of 4 μg/ml was not observed until after 33 days of passage. Mutant characterization revealed that ciprofloxacin-passaged cultures with MICs of 256 to 512 μg/ml carried only 2 or 3 quinolone resistance-determining region (QRDR) mutations. Cultures passaged with JNJ-Q2 selection for up to 51 days displayed MICs of 1 to 64 μg/ml and carried between 4 and 9 target mutations. Established in vitro biofilms of wild-type or ciprofloxacin-resistant MRSA exposed to JNJ-Q2 displayed greater decreases in bacterial counts (7 days of exposure produced 4.5 to 〉 7 log 10 CFU decreases) than biofilms exposed to ciprofloxacin, moxifloxacin, rifampin, or vancomycin.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00470-11
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2011
    detail.hit.zdb_id: 1496156-8
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  • 4
    Online Resource
    Online Resource
    Synergistic Activity of Ceftobiprole and Vancomycin in a Rat Model of Infective Endocarditis Caused by Methicillin-Resistant and Glycopeptide-Intermediate Staphylococcus aureus
    American Society for Microbiology ; 2012
    In:  Antimicrobial Agents and Chemotherapy Vol. 56, No. 3 ( 2012-03), p. 1476-1484
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 56, No. 3 ( 2012-03), p. 1476-1484
    Abstract: The therapeutic activity of ceftobiprole medocaril, the prodrug of ceftobiprole, was compared to that of vancomycin, daptomycin, and the combination of a subtherapeutic dose of ceftobiprole and vancomycin in a rat model of infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) (ATCC 43300) or glycopeptide-intermediate Staphylococcus aureus (GISA) (NRS4 and HIP 5836) strains. The minimum bactericidal concentrations of ceftobiprole, vancomycin, and daptomycin at bacterial cell densities similar to those encountered in the cardiac vegetation in the rat endocarditis model were 2, 〉 64, and 8 μg/ml, respectively, for MRSA ATCC 43300 and 4, 〉 64, and 8 μg/ml, respectively, for the GISA strain. Ceftobiprole medocaril administered in doses of 100 mg/kg of body weight given intravenously (i.v.) twice a day (BID) every 8 h (q8h) (equivalent to a human therapeutic dose of ceftobiprole [500 mg given three times a day [TID]) was the most effective monotherapy, eradicating nearly 5 log 10 CFU/g MRSA or 6 log 10 CFU/g GISA organisms from the cardiac vegetation and had the highest incidence of sterile vegetation compared to the other monotherapies in the endocarditis model. In in vitro time-kill studies, synergistic effects were observed with ceftobiprole and vancomycin on MRSA and GISA strains, and in vivo synergy was noted with combinations of subtherapeutic doses of these agents for the same strains. Additionally, sterile vegetations were achieved in 33 and 60%, respectively, of the animals infected with MRSA ATCC 43300 or GISA NRS4 receiving ceftobiprole-vancomycin combination therapy. In summary, ceftobiprole was efficacious both as monotherapy and in combination with vancomycin in treating MRSA and GISA infections in a rat infective endocarditis model and warrants further evaluation.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.06057-11
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2012
    detail.hit.zdb_id: 1496156-8
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  • 5
    Online Resource
    Online Resource
    Clinical Pharmacokinetics of Alamifovir and Its Metabolites
    American Society for Microbiology ; 2005
    In:  Antimicrobial Agents and Chemotherapy Vol. 49, No. 5 ( 2005-05), p. 1813-1822
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 49, No. 5 ( 2005-05), p. 1813-1822
    Abstract: Alamifovir, a purine nucleotide analogue prodrug, and its hydrolyzed derivatives have shown preclincal efficacy activity against wild-type and lamivudine-resistant hepatitis B virus. Two studies were conducted to examine the single- and multiple-dose alamifovir pharmacokinetics after oral administration in healthy males. In study 1, subjects were given single doses (0.2 to 80 mg), with a subset receiving 20 mg in a fed state. Study 2 subjects were dosed with 2.5 to 15 mg twice daily for 15 days. Plasma samples were collected over 72 h in study 1 and over 24 h on days 1 and 15 in study 2. Concentrations of alamifovir and its major metabolites were determined using liquid chromatography/tandem mass spectrometry methods. The data were analyzed using a noncompartmental technique. Although alamifovir was rapidly absorbed, there was limited systemic exposure due to its rapid hydrolysis and formation of at least three metabolites, suggesting that alamifovir acts as a prodrug. The major metabolites detected were 602074 and 602076, with 602075 detectable only in higher-dose groups. Maximum 602074 plasma concentration was achieved at approximately 0.5 h ( T max ) and declined with a 1- to 2-h terminal half-life ( t 1/2 ). Maximum concentrations of 602076 ( C max ) averaged 10% of the 602074 C max and reached T max in 2.5 h with a 4-h t 1/2 . Food appeared to decrease the extent of absorption of the compound. Multiple dosing resulted in minimal accumulation, and the concentrations following multiple doses could be predicted using the single-dose data. Alamifovir was well tolerated and the pharmacokinetics were characterized in these studies.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.49.5.1813-1822.2005
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2005
    detail.hit.zdb_id: 1496156-8
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  • 6
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    Online Resource
    Activity of a Potent Hepatitis C Virus Polymerase Inhibitor in the Chimpanzee Model
    American Society for Microbiology ; 2007
    In:  Antimicrobial Agents and Chemotherapy Vol. 51, No. 12 ( 2007-12), p. 4290-4296
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 51, No. 12 ( 2007-12), p. 4290-4296
    Abstract: A-837093 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase. It possesses nanomolar potencies in both enzymatic and replicon-based cell culture assays. In rats and dogs this compound demonstrated an oral plasma half-life of greater than 7 h, and its bioavailability was 〉 60%. In monkeys it had a half-life of 1.9 h and 15% bioavailability. Its antiviral efficacy was evaluated in two chimpanzees infected with HCV in a proof-of-concept study. The design included oral dosing of 30 mg per kg of body weight twice a day for 14 days, followed by a 14-day posttreatment observation. Maximum viral load reductions of 1.4 and 2.5 log 10 copies RNA/ml for genotype 1a- and 1b-infected chimpanzees, respectively, were observed within 2 days after the initiation of treatment. After this initial drop in the viral load, a rebound of plasma HCV RNA was observed in the genotype 1b-infected chimpanzee, while the genotype 1a-infected chimpanzee experienced a partial rebound that lasted throughout the treatment period. Clonal analysis of NS5B gene sequences derived from the plasma of A-837093-treated chimpanzees revealed the presence of several mutations associated with resistance to A-837093, including Y448H, G554D, and D559G in the genotype 1a-infected chimpanzee and C316Y and G554D in the genotype 1b-infected chimpanzee. The identification of resistance-associated mutations in both chimpanzees is consistent with the findings of in vitro selection studies, in which many of the same mutations were selected. These findings validate the antiviral efficacy and resistance development of benzothiadiazine HCV polymerase inhibitors in vivo.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00723-07
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2007
    detail.hit.zdb_id: 1496156-8
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  • 7
    Online Resource
    Online Resource
    In Vitro Antibacterial Activities of JNJ-Q2, a New Broad-Spectrum Fluoroquinolone
    American Society for Microbiology ; 2010
    In:  Antimicrobial Agents and Chemotherapy Vol. 54, No. 5 ( 2010-05), p. 1955-1964
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 54, No. 5 ( 2010-05), p. 1955-1964
    Abstract: JNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae , including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC 90 value for JNJ-Q2 of 0.12 μg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus (MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC 90 value was 0.25 μg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2× and 4× MIC levels against clinical isolates of S. pneumoniae and MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA , parC , or gyrA plus parC mutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2× and 4× MICs in S. pneumoniae , MRSA, and Escherichia coli were indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitro that is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01374-09
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2010
    detail.hit.zdb_id: 1496156-8
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  • 8
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    Praziquantel Affects the Regulatory Myosin Light Chain of Schistosoma mansoni
    American Society for Microbiology ; 2009
    In:  Antimicrobial Agents and Chemotherapy Vol. 53, No. 3 ( 2009-03), p. 1054-1060
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 53, No. 3 ( 2009-03), p. 1054-1060
    Abstract: Praziquantel (PZQ) is the drug of choice for schistosomiasis and probably is the only highly effective drug currently available for treating schistosomiasis-infected individuals. The mode of action of PZQ involves increasing the calcium uptake of the parasite, resulting in tegumental damage and death of the parasite. Despite its remarkable function, the target of PZQ has not been identified yet. To begin to understand where PZQ acts, in this study we expressed the cDNA library of Schistosoma mansoni on the surface of T7 bacteriophages and screened this library with labeled PZQ. This procedure identified a clone that strongly bound to PZQ. Subsequent DNA analysis of inserts showed that the clone coded for regulatory myosin light chain protein. The gene was then cloned, and recombinant S. mansoni myosin light chain (SmMLC) was expressed. Immunoblot analysis using antibodies raised to recombinant SmMLC (rSmMLC) showed that SmMLC is abundantly expressed in schistosomula and adult stages compared to the amount in cercarial stages. In vitro analyses also confirmed that PZQ strongly binds to rSmMLC. Further, peptide mapping studies showed that PZQ binds to amino acids 46 to 76 of SmMLC. Immunoprecipitation analysis confirmed that SmMLC is phosphorylated in vivo upon exposure to PZQ. Interestingly, significant levels of anti-SmMLC antibodies were present in vaccinated mice compared to the amount in infected mice, suggesting that SmMLC may be a potential target for protective immunity in schistosomiasis. These findings suggest that PZQ affects SmMLC function, and this may have a role in PZQ action.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01222-08
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2009
    detail.hit.zdb_id: 1496156-8
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  • 9
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    Rapid and Sensitive Liquid Chromatography/Mass Spectrometry Assay for Caspofungin in Human Aqueous Humor
    American Society for Microbiology ; 2010
    In:  Antimicrobial Agents and Chemotherapy Vol. 54, No. 10 ( 2010-10), p. 4467-4470
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 54, No. 10 ( 2010-10), p. 4467-4470
    Abstract: A rapid, precise, and sensitive liquid chromatography/mass spectrometry (LC/MS) method to quantify the caspofungin concentration in human aqueous humor was developed and validated. Sample preparation involved simple dilution of aqueous humor samples with acetonitrile. Azithromycin was the internal standard. Good linearity over 10 to 5,000 ng/ml was observed. The lower limit of quantification was 10 ng/ml. The intra- and interday accuracies (percent bias) were within 11%, while the intra- and interday precisions were within 6%.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00509-10
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2010
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
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  • 10
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    Enhancement of Antimicrobial Activity against Pseudomonas aeruginosa by Coadministration of G10KHc and Tobramycin
    American Society for Microbiology ; 2006
    In:  Antimicrobial Agents and Chemotherapy Vol. 50, No. 11 ( 2006-11), p. 3833-3838
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 50, No. 11 ( 2006-11), p. 3833-3838
    Abstract: Pseudomonas aeruginosa is a common opportunistic human pathogen that is associated with life-threatening acute infections and chronic airway colonization during cystic fibrosis. Previously, we converted the wide-spectrum antimicrobial peptide novispirin G10 into a s electively- t argeted a nti m icrobial p eptide (STAMP), G10KHc. Compared to novispirin G10, the STAMP had an enhanced ability to kill Pseudomonas mendocina . In this study, we explored the activity of G10KHc against P. aeruginosa . G10KHc was found to be highly active (as active as tobramycin) against P. aeruginosa clinical isolates. Most interestingly, we observed a synergistic-like enhancement in killing activity when biofilms and planktonic cultures of P. aeruginosa were cotreated with G10KHc and tobramycin. The data indicate that the mechanism of enhanced activity may involve increased tobramycin uptake due to G10KHc-mediated cell membrane disruption. These results suggest that G10KHc may be useful against P. aeruginosa during acute and chronic infection states, especially when it is coadministered with tobramycin.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00509-06
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2006
    detail.hit.zdb_id: 1496156-8
    detail.hit.zdb_id: 217602-6
    SSG: 12
    SSG: 15,3
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