Abstract:
:When developing novel microbicide products for the prevention of HIV infection, the preclinical safety program must evaluate not only the active pharmaceutical ingredient but also the product itself. To that end, we applied several relatively standard toxicology study methodologies to female sheep, incorporating an assessment of the pharmacokinetics, safety, tolerability, and local toxicity of a dapivirine-containing human vaginal ring formulation (Dapivirine Vaginal Ring-004). We performed a 3-month general toxicology study, a preliminary pharmacokinetic study using drug-loaded vaginal gel, and a detailed assessment of the kinetics of dapivirine delivery to plasma, vaginal, and rectal fluid and rectal, vaginal, and cervical tissue over 28 days of exposure and 3 and 7 days after removal of the ring. The findings of the general toxicology study supported the existing data from both preclinical and clinical studies in that there were no signs of toxicity related to dapivirine. In addition, the presence of the physical dapivirine ring did not alter local or systemic toxicity or the pharmacokinetics of dapivirine. Pharmacokinetic studies indicated that the dapivirine ring produced significant vaginal tissue levels of dapivirine. However, no dapivirine was detected in cervical tissue samples using the methods described here. Plasma and vaginal fluid levels were lower than those in previous clinical studies, while there were detectable dapivirine levels in the rectal tissue and fluid. All tissue and fluid levels tailed off rapidly to undetectable levels following removal of the ring. The sheep represents a very useful model for the assessment of the safety and pharmacokinetics of microbicide drug delivery devices, such as the vaginal ring.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Holt JD,Cameron D,Dias N,Holding J,Muntendam A,Oostebring F,Dreier P,Rohan L,Nuttall Jdoi
10.1128/AAC.04954-14subject
Has Abstractpub_date
2015-07-01 00:00:00pages
3761-70issue
7eissn
0066-4804issn
1098-6596pii
AAC.04954-14journal_volume
59pub_type
杂志文章abstract::Colistin is increasingly being utilized against Gram-negative pathogens, including Pseudomonas aeruginosa, resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated killing of Pseudomonas aeruginosa by colistin at several CFUo and devel...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00881-09
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更新日期:2010-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1128/aac.5.3.323
更新日期:1974-03-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/aac.34.9.1773
更新日期:1990-09-01 00:00:00
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abstract::Phosphonoformate (PF) at a concentration of 5 to 10 mug/ml inhibited the growth of type 1 strains of herpes simplex virus (HSV) in tissue culture, whereas 20 to 30 mug/ml was required for inhibition of type 2 strains and about 50 mug/ml was required for murine cytomegalovirus. In mice inoculated intraperitoneally or i...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.14.6.817
更新日期:1978-12-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01884-15
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.27.2.224
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.7.1121
更新日期:1989-07-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.8.6.679
更新日期:1975-12-01 00:00:00
abstract::The antimicrobial activity of CP-62,993 against four Chlamydia trachomatis isolates was compared with those of erythromycin, clindamycin, and tetracycline. The MIC of CP-62,993 was 0.26 to 1.02 micrograms/ml for 100% inclusion inhibition and 0.031 to 0.063 microgram/ml for 50% inclusion inhibition. With pharmacokineti...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.5.811
更新日期:1987-05-01 00:00:00
abstract::For six clinical isolates of Chlamydia trachomatis, in vitro susceptibility to erythromycin, azithromycin, and josamycin has been determined. Four isolates were resistant to all the antibiotics and had the mutations A2058C and T2611C (Escherichia coli numbering) in the 23S rRNA gene. All the isolates had mixed populat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.48.4.1347-1349.2004
更新日期:2004-04-01 00:00:00
abstract::Five R plasmids transferred from Asian strains of Vibrio cholerae all proved to be members of compatibility group C. A non-self-transmissible plasmid, stable in V. cholerae, was mobilized for transfer to Escherichia coli K-12 and found to be unstably inherited in that host. Plasmids of group C and P transferred to a w...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.11.4.585
更新日期:1977-04-01 00:00:00
abstract::The dynamic interaction of planktonic and biofilm cells of mucoid Pseudomonas aeruginosa with tobramycin and piperacillin was investigated in a chemostat system. The results indicated that planktonic and young biofilm cells of the 2-day-old chemostat culture of P. aeruginosa were susceptible to killing by chemostat-co...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.36.6.1208
更新日期:1992-06-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02501-17
更新日期:2018-04-26 00:00:00
abstract::Bacillus subtilis strain 168 produces the extremely stable and broad-spectrum lantibiotic sublancin 168. Known sublancin 168-susceptible organisms include important pathogens, such as Staphylococcus aureus. Nevertheless, since its discovery, the mode of action of sublancin 168 has remained elusive. The present studies...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00439-09
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.26.2.164
更新日期:1984-08-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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abstract::The candidacidal activity of nitric oxide (NO) as delivered by a class of compounds termed diazeniumdiolates has been investigated. Diazeniumdiolates are stable agents capable of releasing NO in a biologically usable form at a predicted rate, and three such compounds were examined for activity. One compound, (Z)-1-[N-...
journal_title:Antimicrobial agents and chemotherapy
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doi:10.1128/AAC.42.9.2342
更新日期:1998-09-01 00:00:00
abstract::The Capnocytophaga sputigena isolate NOR, responsible for septicemia, was resistant to amoxicillin and narrow-spectrum cephalosporins. In a cloning experiment, a new gene, bla(CSP-1), was identified; this gene encodes a novel extended-spectrum beta-lactamase (ESBL) that shares only 52% and 49% identities with the CME-...
journal_title:Antimicrobial agents and chemotherapy
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abstract::Carbapenemases are among the newest resistance mechanisms to emerge in some gram-negative bacteria. We describe bacteremia in a critically ill liver transplant recipient infected with KPC-2-producing Enterobacter cloacae and Pseudomonas putida. Although this enzyme has been previously described in Enterobacter spp., t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:2009-01-01 00:00:00
abstract::The in vitro activity of MDL 62,879, a new peptide antibiotic that inhibits protein synthesis through an interaction with elongation factor Tu, against a wide range of recent clinical isolates of common aerobic gram-positive and anaerobic organisms was determined. MDL 62,879 was highly active against staphylococci (MI...
journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:1979-07-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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