Abstract:
:INX-08189 is an aryl-phosphoramidate of 6-O-methyl-2'-C-methyl guanosine. INX-08189 was highly potent in replicon assays, with a 50% effective concentration of 10±6 nM against hepatitis C genotype 1b at 72 h. The inhibitory effect on viral replication was rapid, with a 50% effective concentration (EC50) of 35±8 nM at 24 h. An intracellular 2'-C-methyl guanosine triphosphate (2'-C-MeGTP) concentration of 2.43±0.42 pmol/10(6) cells was sufficient to achieve 90% inhibition of viral replication. In vitro resistance studies confirmed that the S282T mutation in the NS5b gene conferred an approximately 10-fold reduction in sensitivity to INX-08189. However, the complete inhibition of S282T mutant replicons still could be achieved with an EC90 of 344±170 nM. Drug combination studies of INX-08189 and ribavirin indicated significant synergy in antiviral potency both in wild-type and S282T-expressing replicons. Genotype 1b replicons could be cleared after 14 days of culture when exposed to as little as 20 nM INX-08189. No evidence of mitochondrial toxicity was observed after 14 days of INX-08189 exposure in both HepG2 and CEM human cell lines. In vivo studies of rats and cynomolgus monkeys demonstrated that 2'-C-MeGTP concentrations in liver equivalent to the EC90 could be attained after a single oral dose of INX-08189. Rat liver 2'-C-MeGTP concentrations were proportional to dose, sustained for greater than 24 h, and correlated with plasma concentrations of the nucleoside metabolite 2'-C-methyl guanosine. The characteristics displayed by INX-08189 support its continued development as a clinical candidate for the treatment of chronic HCV infection.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Vernachio JH,Bleiman B,Bryant KD,Chamberlain S,Hunley D,Hutchins J,Ames B,Gorovits E,Ganguly B,Hall A,Kolykhalov A,Liu Y,Muhammad J,Raja N,Walters CR,Wang J,Williams K,Patti JM,Henson G,Madela K,Aljarah M,Gillesdoi
10.1128/AAC.01335-10subject
Has Abstractpub_date
2011-05-01 00:00:00pages
1843-51issue
5eissn
0066-4804issn
1098-6596pii
AAC.01335-10journal_volume
55pub_type
杂志文章abstract::We determined the in vitro susceptibilities of 54 isolates of Haemophilus ducreyi from Thailand (29 isolates) and San Francisco (25 isolates) to penicillin G, tetracycline, amoxicillin-clavulanic acid, ceftriaxone, cefixime, erythromycin, azithromycin, ciprofloxacin, ofloxacin, and trimethoprim-sulfamethoxazole. Isola...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.7.1552
更新日期:1993-07-01 00:00:00
abstract::The microbicidal efficacies of two anionic surfactants, sodium lauryl sulfate (SLS) and n-lauroylsarcosine (LS), were evaluated in cultured cells and in a murine model of herpes simplex type 2 (HSV-2) intravaginal infection. In vitro studies showed that SLS and LS were potent inhibitors of the infectivity of HSV-2 str...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.6.1671-1681.2001
更新日期:2001-06-01 00:00:00
abstract::For the present report, a novel complex class 1 integron, In60, was characterized. Part of this integron includes the bla(CTX-M-9) gene and its downstream nucleotide sequence, which shares 81% and 78% nucleotide identity with those of kluA-1 beta-lactamase and orf3 of K. ascorbata, respectively. Furthermore, a new ins...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.8.2656-2661.2002
更新日期:2002-08-01 00:00:00
abstract::We investigated whether cells derived from the fetal central nervous system can support productive infection by a human immunodeficiency virus type 1 (HIV-1) isolate termed UHC-1, produced by a cellular clone derived from HIV-1 strain HIV-IIIB chronically infected U-937 promonocytic cells, and what the effect of nucle...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.6.1305
更新日期:1993-06-01 00:00:00
abstract::The Bacteroides fragilis bacteriocin which inhibits ribonucleic acid (RNA) polymerase activity had a narrow activity spectrum in vivo and only inhibited the growth of certain B. fragilis strains. In vitro the bacteriocin was not specific and inhibited RNA polymerases from widely diverse bacterial genera. RNA polymeras...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.20.4.437
更新日期:1981-10-01 00:00:00
abstract::Vaborbactam (formerly RPX7009) is a member of a new class of β-lactamase inhibitor with pharmacokinetic properties similar to those of many β-lactams, including carbapenems. The pharmacokinetics and safety of vaborbactam were evaluated in 80 healthy adult subjects in a first-in-human randomized, placebo-controlled, do...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.00568-16
更新日期:2016-09-23 00:00:00
abstract::The increasing prevalence of drug-resistant pathogens highlights the need to identify novel antibiotics. Here we investigated the efficacies of four new antimicrobial peptides (AMPs) for potential drug development. The antibacterial activities, synergistic effects, and antibiofilm properties of the four chimeric AMPs ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02473-13
更新日期:2014-01-01 00:00:00
abstract::Prolonged treatment of chronic hepatitis B virus (HBV) infection with lamivudine ([-]-beta-L-2',3'-dideoxy-3' thiacytidine) or famciclovir may select for viral mutants that are drug resistant due to point mutations in the polymerase gene. Determining whether such HBV mutants are sensitive to new antiviral agents is th...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.45.9.2495-2501.2001
更新日期:2001-09-01 00:00:00
abstract::MCC-478 is a newly synthesized 2-amino-6-arylthio-9-phosphonomethoxyethylpurine bis(2,2,2-trifluoroethyl) ester derivative. MCC-478 showed a substantially higher (ca. 80-fold) anti-hepatitis B virus (HBV) activity than that of lamivudine, despite no significant anti-human immunodeficiency virus activity. Since the bis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.46.9.2872-2877.2002
更新日期:2002-09-01 00:00:00
abstract::Because macrolide antibiotics are hypothesized to possess immunomodulatory activity independent of their antimicrobial activity, we evaluated the immunomodulatory effect of clarithromycin in a murine model of lung inflammation induced by either live or UV-killed Mycoplasma pneumoniae. BALB/c mice were intranasally ino...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.5.1614-1620.2003
更新日期:2003-05-01 00:00:00
abstract::Forty years after the last endemic smallpox case, variola virus (VARV) is still considered a major threat to humans due to its possible use as a bioterrorism agent. For many years, the risk of disease reemergence was thought to solely be through deliberate misuse of VARV strains kept in clandestine laboratories. Howev...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,评审
doi:10.1128/AAC.01683-19
更新日期:2020-03-24 00:00:00
abstract::Azithromycin concentrations in the tonsils of 56 pediatric patients, treated with 10 or 20 mg of the drug per kg of body weight for 3 days, were compared. Azithromycin levels in plasma and tonsil samples were determined up to 8.5 days after the last dose. The 20-mg/kg regimen resulted in an improved tonsillar distribu...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.46.5.1594-1596.2002
更新日期:2002-05-01 00:00:00
abstract::The potential of bacteriophage therapy to treat infections caused by antibiotic-resistant bacteria has now been well established using various animal models. While numerous newly isolated bacteriophages have been claimed to be potential therapeutic candidates on the basis of in vitro observations, the parameters used ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01596-13
更新日期:2013-12-01 00:00:00
abstract::Norfloxacin is a quinolone (pyridonecarboxylic acid derivative) effective against Pseudomonas aeruginosa infections. We studied the effects of this drug on DNA metabolism in P. aeruginosa. Norfloxacin inhibits DNA replication immediately on its addition to a logarithmically growing culture of P. aeruginosa. It inhibit...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.29.1.1
更新日期:1986-01-01 00:00:00
abstract::The elimination kinetics of cefotetan (YM09330), a new parenteral semisynthetic cephamycin derivative, were studied in eight healthy volunteers and 41 patients with renal insufficiency after the administration of a single 500-mg dose intravenously. Concentrations of cefotetan in serum and urine were determined by both...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.23.1.31
更新日期:1983-01-01 00:00:00
abstract::The biosynthetic gene cluster of lankamycin (LM), a 14-member macrolide antibiotic, is encoded on the 210-kb linear plasmid pSLA2-L in Streptomyces rochei 7434AN4. LM contains a 3-hydroxy-2-butyl group at the C-13 position, which is different from an ethyl group in erythromycin. The following two possibilities could b...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00016-06
更新日期:2006-06-01 00:00:00
abstract::We studied the effects of two N,N'-bis(benzyl)-substituted polyamine analogs on the capacities of Trypanosoma cruzi to invade and multiply within a mammalian host cell. At concentrations as low as 1 microM, these compounds reduced significantly the infectivity of the parasite for rat heart myoblasts in a time-dependen...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.10.2235
更新日期:1993-10-01 00:00:00
abstract::Prior investigators have reported a broad gram-negative spectrum and a marked anti-Pseudomonas activity in vitro with BL-P1654, 6-[R-alpha-(guanylureido)phenylacetamido]-penicillanic acid. An in vitro comparison of BL-P1654 to carbenicillin was performed against 84 strains of Pseudomonas and 39 strains of Enterobacter...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.6.5.643
更新日期:1974-11-01 00:00:00
abstract::Telavancin displays potent in vitro and in vivo activity against methicillin-resistant Staphylococcus aureus (MRSA), including strains with reduced susceptibility to vancomycin. We compared the efficacies of telavancin and vancomycin against MRSA strains with vancomycin MICs of ≥1 μg/ml in a neutropenic murine lung in...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00062-10
更新日期:2010-12-01 00:00:00
abstract::Though the primary action of the cationic antibiotic polymyxin B is against the membrane of susceptible bacteria, severe morphological changes are detected in the cytoplasm. Using fluorescence microscopy and a mono-N-dansyl-polymyxin B derivative, we could demonstrate aggregations of the antibiotic with cellular mater...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.8.1.95
更新日期:1975-07-01 00:00:00
abstract::Mammalian serum amyloid A (SAA) is a major acute phase protein that shows a massive increase in plasma concentration during inflammation. In the present study, we demonstrate that the expression of mouse SAA1 in serum was increased when infected with Candida albicans, a major human fungal pathogen, in a systemic infec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01975-19
更新日期:2019-12-20 00:00:00
abstract::Acyclovir-resistant clinical isolates of herpes simplex virus type 1 (HSV-1) were analyzed in vitro for their susceptibilities to essential oils of ginger, thyme, hyssop, and sandalwood. All essential oils exhibited high levels of virucidal activity against acyclovir-sensitive strain KOS and acyclovir-resistant HSV-1 ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00426-06
更新日期:2007-05-01 00:00:00
abstract::Tigemonam, a new monobactam with excellent activity against gram-negative bacteria, was evaluated for in vivo efficacy and absorption after oral administration to laboratory animals. Tigemonam is absorbed when administered orally to mice and dogs. In a variety of gram-negative systemic infections in mice, orally admin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.2.226
更新日期:1987-02-01 00:00:00
abstract::The biliary excretion profile of cefixime was studied in 10 patients provided with T-tube drainage of the common bile duct after cholecystectomy. Following a single 200-mg oral dose, the peak concentration of cefixime in bile reached 56.9 +/- 70 mg/liter, approximately 20 times as high as the peak concentration in ser...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.37.7.1488
更新日期:1993-07-01 00:00:00
abstract::A total of 6,991 unique patient isolates of Streptococcus pneumoniae were collected from October 1997 to June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among these isolates, 20.2% were penicillin nonsusceptible, with 14.6% being penicillin intermediate (MIC, 0.12 to 1 microg/ml) and 5.6% being pe...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.6.1867-1874.2003
更新日期:2003-06-01 00:00:00
abstract::The topical delivery of liposomally encapsulated interferon was evaluated in the cutaneous herpes simplex virus guinea pig model. Application of liposomally entrapped interferon caused a reduction of lesion scores, whereas application of interferon formulated as a solution or as an emulsion was ineffective. The method...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.8.1217
更新日期:1989-08-01 00:00:00
abstract::CMY-30, a Val211Gly mutant of CMY-2 cephalosporinase, was derived by mutagenesis. The hydrolytic efficiency of CMY-30 against expanded-spectrum cephalosporins was higher than that of CMY-2 due to increased k(cat) values. Findings indicate a role of the Omega loop residue 211 in determining the substrate specificities ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00219-09
更新日期:2009-08-01 00:00:00
abstract::Human immunodeficiency virus type 1 (HIV-1) produces two polyproteins, Pr55(Gag) and Pr160(Gag-Pol), that are cleaved into mature functional subunits by the virally encoded protease. Drugs that inhibit this protease are an important part of anti-HIV therapy. We studied the ordered accumulation of Gag and Gag-Pol proce...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.5.1397-1403.2000
更新日期:2000-05-01 00:00:00
abstract::Clinical pharmacological studies of ticarcillin (alpha-carboxyl-3-thienylmethyl penicillin, BRL-2288) were conducted in patients with metastatic cancer and leukemia. After administration of 0.5 g intramuscularly, 1 g intramuscularly, and 1 g intravenously, the mean peak concentrations in serum were 18, 35, and 106 mug...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.4.1.31
更新日期:1973-07-01 00:00:00
abstract::The in vitro antimicrobial activity of O-demethylfortimicin A (ODMF), a derivative of fortimicin A, was compared with those of fortimicin A and gentamicin against a spectrum of 256 organisms. All three antibiotics were active in low concentrations against all strains of Enterobacteriaceae, Acinetobacter sp., and Staph...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.18.5.766
更新日期:1980-11-01 00:00:00