title: Vaginal Microbicide Film Combinations of Two Reverse Transcriptase Inhibitors, EFdA and CSIC, for the Prevention of HIV-1 Sexual Transmission.
abstract: OBJECTIVE
  EFdA is a potent nucleoside reverse transcriptase inhibitor (NRTI) with activity against a wide spectrum of wild-type and drug resistant HIV-1 variants. CSIC is a tight-binding non-nucleoside reverse transcriptase inhibitor (NNRTI) with demonstrated anti-HIV properties important for use in topical prevention of HIV transmission. The objective of this study was to develop and characterize film-formulated EFdA and CSIC for use as a female-controlled vaginal microbicide to prevent sexual transmission of HIV.
  
  
  METHODS
  Assessments of EFdA- and CSIC-loaded films included physicochemical characteristics, in vitro cytotoxicity, epithelia integrity studies, compatibility with the normal vaginal Lactobacillus flora and anti-HIV bioactivity evaluations.
  
  
  RESULTS
  No significant change in physicochemical properties or biological activity of the combination films were noted during 3 months storage. In vitro cytotoxicity and bioactivity testing showed that 50% cytotoxic concentration (CC50) of either EFdA or CSIC was several orders of magnitude higher than the 50% effective concentration (EC50) values. Film-formulated EFdA and CSIC combination showed additive inhibitory activity against wild type and drug-resistant variants of HIV. Epithelial integrity studies demonstrated that the combination vaginal film had a much lower toxicity to HEC-1A monolayers compared to that of VCF®, a commercial vaginal film product containing nonoxynol-9. Polarized ectocervical explants showed films with drug alone or in combination were effective at preventing HIV infection.
  
  
  CONCLUSIONS
  Our data suggest that vaginal microbicide films containing a combination of the NRTI EFdA and the NNRTI CSIC have potential to prevent HIV-1 sexual transmission.
authors: Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, 15213, USA.
authors: Wei
authors: W
authors: Zhang
authors: Minlu
authors: M
authors: Hu
authors: Yuan
authors: Y
authors: Shi
authors: Tiantian
authors: T
authors: Gong
authors: Charlene S
authors: CS
authors: Dezzutti
authors: Bernard
authors: B
authors: Moncla
authors: Stefan G
authors: SG
authors: Sarafianos
authors: Michael A
authors: MA
authors: Parniak
authors: Lisa C
authors: LC
authors: Rohan
mesh_terms: D000282:Administration, Intravaginal; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D002460:Cell Line; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003979:Diazonium Compounds / Q000494:pharmacology*; D004359:Drug Therapy, Combination / Q000379:methods; D005204:Farnesol / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007778:Lactobacillus / Q000187:drug effects; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014621:Vagina / Q000382:microbiology*
chemical_list: D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D003979:Diazonium Compounds; D007211:Indoles; D018894:Reverse Transcriptase Inhibitors; C040772:epoxyfarnesyl diazoacetate; C083192:5-chloro-3-phenylthioindole-2-carboxamide; D005204:Farnesol