bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1
Authors: Szczech G. M. , Furman P. , Painter G. R. , Barry D. W. , Borroto-Esoda K. , Grizzle T. B. , Blum M. R. , Sommadossi J.-P. , Endoh R. , Niwa T. , Yamamoto M. , Moxham C. 
Published: April 2009

ABSTRACTEmivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [14C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.
Chemical Specificity of thePDR5Multidrug Resistance Gene Product ofSaccharomyces cerevisiaeBased on Studies with Tri-n-Alkyltin Chlorides
Authors: Golin John , Barkatt Alisa , Cronin Susan , Eng George , May Leopold 
Published: April 2009

ABSTRACTTo understand the chemical basis of action for thePDR5-encoded multidrug resistance transporter ofSaccharomyces cerevisiae, we compared the relative hypersensitivities of the wild-type (RW2802) and null mutant strains toward a series of tri-n-alkyltin compounds. These compounds differ from each other in a systematic fashion—either by hydrocarbon chain length or by anion composition. Using zone-of-inhibition and fixed-concentration assays, we found that the ethyl, propyl, and butyl compounds are strongPDR5substrates, whereas the methyl and pentyl compounds are weak. We conclude that hydrophobicity and anion makeup are relatively unimportant factors in determining whether a tri-n-alkyltin compound is a goodPDR5substrate but that the dissociation of the compound and the molecular size are significant.
Effect of Zinc-Reversible Growth-Inhibitory Activity in Human Empyema Fluid on Antibiotic Microbicidal Activity
Authors: Sohnle Peter G. , Hahn Beth L. 
Published: April 2009

ABSTRACT

Abscess fluid supernatants have zinc-reversible microbial growth-inhibitory activity that is mediated by calprotectin, a zinc-binding protein. Because it inhibits microbial growth, this activity might interfere with killing by antibiotics that require their target organisms to be proliferating. In the present study, we cultured bacteria in human empyema fluid and used zinc to overcome the growth-inhibitory effect of calprotectin. We then compared the effect of zinc on killing by the beta-lactams ampicillin and cefazolin with that of the fluoroquinolone trovafloxacin, since the latter may be better able to kill nonproliferating organisms. In empyema fluid diluted 1:5 in normal saline, addition of zinc (30 μM) increased growth of two strains of
Staphyloccocus aureus
and two strains of
Escherichia coli
but did not affect the MICs or MBCs of the three antibiotics in Mueller-Hinton broth. For one strain of
S. aureus
, no effect of zinc was found on killing by either ampicillin or cefazolin. However, with the other strain of
S. aureus
and both strains of
E. coli
, significant enhancement of killing by both drugs was observed with zinc addition. On the other hand, no effect on the killing of any of the organisms was observed for trovafloxacin when zinc was added. These results suggest that the zinc-reversible growth-inhibitory activity of abscess fluid may interfere with the microbicidal activity of antibiotics requiring proliferating target organisms, although antibiotics better able to kill nonproliferating organisms may be less affected by this phenomenon.
Immunosuppressive and Nonimmunosuppressive Cyclosporine Analogs Are Toxic to the Opportunistic Fungal PathogenCryptococcus neoformansvia Cyclophilin-Dependent Inhibition of Calcineurin
Authors: Cruz M. Cristina , Del Poeta Maurizio , Wang Ping , Wenger Roland , Zenke Gerhard , Quesniaux Valerie F. J. , Movva N. Rao , Perfect John R. , Cardenas Maria E. , Heitman Joseph 
Published: April 2009

ABSTRACTCyclosporine (CsA) is an immunosuppressive and antimicrobial drug which, in complex with cyclophilin A, inhibits the protein phosphatase calcineurin. We recently found thatCryptococcus neoformansgrowth is resistant to CsA at 24°C but sensitive at 37°C and that calcineurin is required for growth at 37°C and pathogenicity. Here CsA analogs were screened for toxicity againstC. neoformansin vitro. In most cases, antifungal activity was correlated with cyclophilin A binding in vitro and inhibition of the mixed-lymphocyte reaction and interleukin 2 production in cell culture. Two unusual nonimmunosuppressive CsA derivatives, (γ-OH) MeLeu4-Cs (211-810) and D-Sar (α-SMe)3Val2-DH-Cs (209-825), which are also toxic toC. neoformanswere identified. These CsA analogs inhibitC. neoformansvia fungal cyclophilin A and calcineurin homologs. Our findings identify calcineurin as a novel antifungal drug target and suggest nonimmunosuppressive CsA analogs warrant investigation as antifungal agents.
Activities of the Triazole Derivative SCH 56592 (Posaconazole) against Drug-Resistant Strains of the Protozoan Parasite
Trypanosoma
(
Schizotrypanum
)
cruzi
in Immunocompetent and Immunosuppressed Murine Hosts
Authors: Molina Judith , Martins-Filho Olindo , Brener Zigman , Romanha Alvaro J. , Loebenberg David , Urbina Julio A. 
Published: April 2009

ABSTRACT

We have studied the in vivo activity of the new experimental triazole derivative SCH 56592 (posaconazole) against a variety of strains of the protozoan parasite
Trypanosoma
(
Schizotrypanum
)
cruzi
, the causative agent of Chagas' disease, in both immunocompetent and immunosuppressed murine hosts. The
T. cruzi
strains used in the study were previously characterized as susceptible (CL), partially resistant (Y), or highly resistant (Colombiana, SC-28, and VL-10) to the drugs currently in clinical use, nifurtimox and benznidazole. Furthermore, all strains are completely resistant to conventional antifungal azoles, such as ketoconazole. In the first study, acute infections with the CL, Y, and Colombiana strains in both normal and cyclophosphamide-immunosuppressed mice were treated orally, starting 4 days postinfection (p.i.), for 20 consecutive daily doses. The results indicated that in immunocompetent animals SCH 56592 at 20 mg/kg of body weight/day provided protection (80 to 90%) against death caused by all strains, a level comparable or superior to that provided by the optimal dose of benznidazole (100 mg/kg/day). Evaluation of parasitological cure revealed that SCH 56592 was able to cure 90 to 100% of the surviving animals infected with the CL and Y strains and 50% of those which received the benznidazole- and nifurtimox-resistant Colombiana strain. Immunosuppression markedly reduced the mean survival time of untreated mice infected with any of the strains, but this was not observed for the groups which received SCH 56592 at 20 mg/kg/day or benznidazole at 100 mg/kg/day. However, the overall cure rates were higher for animals treated with SCH 56592 than among those treated with benznidazole. The results were confirmed in a second study, using the same model but a longer (43-dose) treatment period. Finally, a model for the chronic disease in which oral treatment was started 120 days p.i. and consisted of 20 daily consecutive doses was investigated. The results showed that SCH 56592 at 20 mg/kg/day was able to induce a statistically significant increase in survival of animals infected with all strains, while benznidazole at 100 mg/kg/day was able to increase survival only in animals infected with the Colombiana strain. Moreover, the triazole was able to induce parasitological cures in 50 to 60% of surviving animals, irrespective of the infecting strain, while no cures were obtained with benznidazole. Taken together, the results demonstrate that SCH 56592 has in vivo trypanocidal activity, even against
T. cruzi
strains naturally resistant to nitrofurans, nitroimidazoles, and conventional antifungal azoles, and that this activity is retained to a large extent in immunosuppressed hosts.
Ciprofloxacin, Lomefloxacin, or Levofloxacin as Treatment for Chronic Osteomyelitis
Authors: Greenberg Richard N. , Newman Michael T. , Shariaty Saeed , Pectol Richard W. 
Published: April 2009

ABSTRACT
The efficacy and safety of three oral fluoroquinolones (lomefloxacin, levofloxacin, and ciprofloxacin) for the treatment of chronic osteomyelitis were analyzed. Twenty-seven patients had documented infections with quinolone-sensitive organisms and received either lomefloxacin, levofloxacin, or ciprofloxacin. Levofloxacin was effective therapy for 9 of 15 (60%) patients. Lomefloxacin was effective therapy for five of seven (71%) patients, and ciprofloxacin was effective therapy for two of five patients (40%). Average follow-up was 11.8 months for patients who completed the course of therapy, and the average duration of therapy was 60.6 days. Gram-positive bacteria were isolated from 18 patients, and 11 patients were cured. Oral fluoroquinolones can be safe, effective therapy if they are given for a prolonged course as treatment for infections caused by susceptible gram-positive as well as gram-negative organisms and in combination with adequate surgical debridement.
Successful Treatment with Nitazoxanide of
Enterocytozoon bieneusi
Microsporidiosis in a Patient with AIDS
Authors: Bicart-Sée Alain , Massip Patrice , Linas Marie-Denise , Datry Annick 
Published: April 2009

ABSTRACT

A patient with AIDS and chronic diarrhea caused by
Enterocytozoon bieneusi
was successfully treated with nitazoxanide, producing a complete clinical and parasitological response, while off of antiviral therapy. This suggests that nitazoxanide may be effective in treating microsporidiosis caused by
E. bieneusi
, a disease for which there is no established treatment.
Role of Penicillin-Binding Proteins in the Initiation of the AmpC β-Lactamase Expression in
Enterobacter cloacae
Authors: Pfeifle Dieter , Janas Eva , Wiedemann Bernd 
Published: April 2009

ABSTRACT

Penicillin-binding proteins (PBPs) are involved in the regulation of β-lactamase expression by determining the level of anhydromuramylpeptides in the periplasmatic space. It was hypothesized that one or more PBPs act as a sensor in the β-lactamase induction pathway. We have performed induction studies with
Escherichia coli
mutants lacking one to four PBPs with
dd
-carboxypeptidase activity. Therefore, we conclude that a strong β-lactamase inducer must inhibit all
dd
-carboxypeptidases as well as the essential PBPs 1a, 1b, and/or 2.
Activities of Masked 2′,3′-Dideoxynucleoside Monophosphate Derivatives against Human Immunodeficiency Virus in Resting Macrophages
Authors: Aquaro Stefano , Wedgwood Orson , Yarnold Christopher , Cahard Dominique , Pathinara Ranjith , McGuigan Christopher , Calio' Raffaele , de Clercq Erik , Balzarini Jan , Perno Carlo Federico 
Published: April 2009

ABSTRACT
The anti-human immunodeficiency virus (HIV) activity of aryloxyphosphoramidate protides of a number of anti-HIV nucleoside analogues was assessed in resting primary monocyte-macrophages (M/M). While 2′,3′-dideoxythymidine (d4T), 2′,3′-dideoxyadenosine (ddA), and 2′,3′-dideoxy-2′,3′-didehydroadenosine (d4A) protides showed an anti-HIV activity that was 25- to 625-fold greater than the parent nucleotides d4T, ddA, and d4A, respectively, other aryloxyphosphoramidate protides showed similar or even lower anti-HIV activities than their parent compounds. This variable anti-HIV effect is most likely related to the different dynamics of intracellular nucleoside monophosphate release from the protides. Our results indicate the potential advantage of therapeutic use of this approach for some nucleotide analogues to affect HIV replication in M/M, one of the major reservoirs of HIV in vivo.
Trovafloxacin Concentrations in Airway Fluids of Patients with Severe Community-Acquired Pneumonia
Authors: Peleman R. A. , Van De Velde V. , Germonpré P. R. , Fleurinck C. , Rosseel M. T. , Pauwels R. A. 
Published: April 2009

ABSTRACTThe penetration of trovafloxacin (TVA), 200 mg once daily, into the airways of 17 patients with severe pneumonia was studied. The mean (standard deviations are given in parentheses) steady-state TVA concentrations, 2 h after the last intake, were 3.1 (0.3) mg/liter in induced sputum (n= 8), 3.2 (1.1) mg/liter in bronchial secretions (n= 9), 3.2 (0.9) mg/liter in bronchoalveolar lavage fluid (n= 10), and 4.9 (1.4) mg/liter in epithelial lining fluid (n= 11).
A Nine-Codon Deletion Mutation in the Cytomegalovirus UL97 Phosphotransferase Gene Confers Resistance to Ganciclovir
Authors: Chou Sunwen , Meichsner Camie L. 
Published: April 2009

ABSTRACT
A deletion mutation (codons 595 to 603) in the cytomegalovirus (CMV) UL97 gene was recently reported after sequence analysis of leukocyte DNA from a patient receiving ganciclovir. The corresponding viral phenotype was examined by transfer of this mutation to a laboratory CMV strain (strain Towne). The recombinant virus was resistant to ganciclovir (8.4-fold increase in the 50% inhibitory concentration), was sensitive to foscarnet, and replicated normally in cell culture.
Susceptibilities of
Neisseria gonorrhoeae
Isolates Containing Amino Acid Substitutions in GyrA, with or without Substitutions in ParC, to Newer Fluoroquinolones and Other Antibiotics
Authors: Tanaka Masatoshi , Nakayama Hiroshi , Haraoka Masashi , Saika Takeshi , Kobayashi Intetsu , Naito Seiji 
Published: April 2009

ABSTRACT

We examined the antimicrobial susceptibilities of 85
Neisseria gonorrhoeae
isolates, classified according to the presence of amino acid substitutions in the GyrA and ParC proteins, to 12 fluoroquinolones and 7 other antibiotics. Sitafloxacin and HSR-903 showed excellent activity against
N. gonorrhoeae
, including strains with both GyrA and ParC substitutions. Among the strains with various GyrA substitutions, strains with a serine-91-to-phenylalanine mutation required the highest MICs of all of the fluoroquinolones tested and were cross-resistant to structurally unrelated β-lactams.
Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTP
Authors: Vaccaro Joseph A. , Parnell K. Mark , Terezakis Stephanie A. , Anderson Karen S. 
Published: April 2009

ABSTRACT
Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2′,3′-didehydro-2′,3′-dideoxythymidine-5′-triphosphate (d4TTP) with the enzyme · primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3′-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.
MICs of Mutacin B-Ny266, Nisin A, Vancomycin, and Oxacillin against Bacterial Pathogens
Authors: Mota-Meira Marilaine , Lapointe Gisèle , Lacroix Christophe , Lavoie Marc C. 
Published: April 2009

ABSTRACT
Peptide antibiotics, particularly lantibiotics, are good candidates for replacing antibiotics to which bacteria have become resistant. In order to compare two such lantibiotics with two antibiotics, the MICs of nisin A, mutacin B-Ny266, vancomycin, and oxacillin against various bacterial pathogens were determined. The results indicate that nisin A and mutacin B-Ny266 are as active as vancomycin and oxacillin against most of the strains tested. Furthermore, mutacin B-Ny266 remains active against strains that are resistant to nisin A, oxacillin, or vancomycin. The wide spectrum of activity of mutacin B-Ny266, its low MICs against bacterial pathogens, and its activity against bacteria resistant to other inhibitors support the development of this substance for therapeutic use.
Efficacies of Topical Formulations of Foscarnet and Acyclovir and of 5-Percent Acyclovir Ointment (Zovirax) in a Murine Model of Cutaneous Herpes Simplex Virus Type 1 Infection
Authors: Piret Jocelyne , Désormeaux André , Gourde Pierrette , Juhász Julianna , Bergeron Michel G. 
Published: April 2009

ABSTRACT
The topical efficacies of foscarnet and acyclovir incorporated into a polyoxypropylene-polyoxyethylene polymer were evaluated and compared to that of 5% acyclovir ointment (Zovirax) by use of a murine model of cutaneous herpes simplex virus type 1 infection. All three treatments given three times daily for 4 days and initiated 24 h after infection prevented the development of the zosteriform rash in mice. The acyclovir formulation and the acyclovir ointment reduced the virus titers below detectable levels in skin samples from the majority of mice, whereas the foscarnet formulation has less of an antiviral effect. Reducing the number of treatments to a single application given 24 h postinfection resulted in a significantly higher efficacy of the formulation of acyclovir than of the acyclovir ointment. Acyclovir incorporated within the polymer was also significantly more effective than the acyclovir ointment when treatment was initiated on day 5 postinfection. The higher efficacy of the acyclovir formulation than of the acyclovir ointment is attributed to the semiviscous character of the polymer, which allows better penetration of the drug into the skin.
Aminoglycoside Resistance in
Mycobacterium kansasii
,
Mycobacterium avium-M. intracellulare
, and
Mycobacterium fortuitum
: Are Aminoglycoside-Modifying Enzymes Responsible?
Authors: Ho I. I. Y. , Chan C. Y. , Cheng A. F. B. 
Published: April 2009

ABSTRACT

Aminoglycoside acetyltransferase was detected in
Mycobacterium kansasii
and
M. fortuitum
but not in
M. avium-M. intracellulare
when they were screened by a radioassay. Aminoglycoside phosphotransferase and nucleotidyltransferase activities were absent from all three species tested. Acetyltransferases from both
M. kansasii
and
M. fortuitum
displayed relatively high

K
m

s, all at the millimolar level, for substrates including tobramycin, neomycin, and kanamycin A. The

K
m

of each substrate was well above the corresponding maximum achievable level in serum. The low affinities of these enzymes for their substrates suggested that drug modification in vivo was very unlikely. Among the various substrates tested, no apparent positive correlation was found between substrate affinity and resistance level. The presence of aminoglycoside-modifying enzymes in these mycobacterial species was therefore not shown to confer resistance to aminoglycosides.
Bacteriologic Efficacies of Oral Azithromycin and Oral Cefaclor in Treatment of Acute Otitis Media in Infants and Young Children
Authors: Dagan Ron , Leibovitz Eugene , Fliss Dan M. , Leiberman Alberto , Jacobs Michael R. , Craig William , Yagupsky Pablo 
Published: April 2009

ABSTRACT

A prospective, open-label, randomized study was conducted in order to determine the bacteriologic efficacies of cefaclor and azithromycin in acute otitis media (AOM). Tympanocentesis was performed on entry into the study and 3 to 4 days after initiation of treatment. Bacteriologic failure after 3 to 4 days of treatment with both drugs occurred in a high proportion of culture-positive patients, especially in those in whom AOM was caused by
Haemophilus influenzae
(16 of 33 [53%] of those treated with azithromycin and 13 of 34 [52%] of those treated with cefaclor). Although a clear correlation of the persistence of the pathogen with increased MICs of the respective drugs could be demonstrated for
Streptococcus pneumoniae
, no such correlation was found for
H. influenzae
. It is proposed that susceptibility breakpoints for
H. influenzae
should be considerably lower than the current ones for both cefaclor and azithromycin for AOM caused by
H. influenzae
.
The CXCR4 Antagonist AMD3100 Efficiently Inhibits Cell-Surface-Expressed Human Immunodeficiency Virus Type 1 Envelope-Induced Apoptosis
Authors: Blanco Julià , Barretina Jordi , Henson Geoffrey , Bridger Gary , De Clercq Erik , Clotet Bonaventura , Esté José A. 
Published: April 2009

ABSTRACTInfection by human immunodeficiency virus type 1 (HIV-1) has been associated with increased cell death by apoptosis in infected and uninfected cells. The envelope glycoprotein complex ([gp120/gp41]n) of X4 HIV-1 isolates is involved in both infected and uninfected cell death via its interaction with cellular receptors CD4 and CXCR4. We studied the effect of the blockade of CXCR4 receptors by the agonist stromal derived factor (SDF-1α) and the antagonist bicyclam AMD3100 on apoptotic cell death of CD4+cells in different models of HIV infection. In HIV-infected CEM or SUP-T1 cultures, AMD3100 showed antiapoptotic activity even when added 24 h after infection. In contrast, other antiviral agents, such as zidovudine, failed to block apoptosis under these conditions. The antiapoptotic activity of AMD3100 was also studied in coculture of peripheral blood mononuclear cells or CD4+cell lines with chronically infected H9/IIIB cells. AMD3100 was found to inhibit both syncytium formation and apoptosis induction with 50% inhibitory concentrations ranging from 0.009 to 0.24 μg/ml, depending on the cell type. When compared to SDF-1α, AMD3100 showed higher inhibitory potency in all cell lines tested. Our data indicate that the bicyclam AMD3100 not only inhibits HIV replication but also efficiently blocks cell-surface-expressed HIV-1 envelope-induced apoptosis in uninfected cells.