Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G

Catalone, Bradley J.; Miller, Shendra R.; Ferguson, Mary; Malamud, Daniel; Kish-Catalone, Tina; Thakkar, Nina; Krebs, Fred C.; Howett, Mary K.; Wigdahl, Brian

doi:10.1016/j.biopha.2005.07.008

Cited by 14 publications

(24 citation statements)

References 19 publications

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“…The standard RVI test protocol includes only one assessment of toxicity at 24 h after the final product application and does not provide for measures of toxicity at more acute post-exposure intervals, particularly the first hours after topical application when sexual intercourse and HIV-1 transmission are likely to occur. Our previous studies using the mouse model of cervicovaginal toxicity demonstrated that N-9- and C31G-mediated damage was greatest at 2 to 4 h post-exposure and was minimal or undetectable by 24 h post-application [19,24,25], presumably because epithelial repair mechanisms had restored the epithelium to its pre-exposure state. The standard RVI model would not reveal these important milestones in the time course of N-9 topical toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…The value of this model system was demonstrated in investigations that reiterated the clinical toxicity of N-9 (after a single application) and paralleled indications of irritation associated with topical application of 1.7% C31G [19,23,24]. Furthermore, mouse model experiments involving topical vaginal application of N-9 clearly demonstrated that (i) N-9-associated tissue damage was greatest approximately two to four hours post-application, (ii) epithelial damage was limited to the cervix, and (iii) repair and regeneration of cervical epithelial tissues was essentially complete 24 h after a single application of N-9 [19].…”

Section: Introductionmentioning

confidence: 99%

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Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety

Lozenski

Ownbey

Wigdahl

et al. 2012

BMC Pharmacol Toxicol

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BackgroundThe disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 (HIV-1) acquisition associated with multiple uses of a nonoxynol-9 (N-9)-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies.MethodsTo evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9.ResultsAfter the initial application of N-9 (aqueous, 1%), considerable damage to the cervical epithelium (but not the vaginal epithelium) was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures (up to 4 days) were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures.ConclusionsRather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre-clinical microbicide development strategies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety

Lozenski

Ownbey

Wigdahl

et al. 2012

BMC Pharmacol Toxicol

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“…We chose pSS as our model compound for this study because of its known antiviral activity and its ease of synthesis (Neurath et al, 2006). Current formulations of pSS expose vaginal tissue to the polymeric drug immediately upon application and may increase susceptibility for inflammation, potentially increasing a woman’s chance of contracting HIV (Catalone et al, 2005; Lard-Whiteford, 2004; Ratterree et al, 2005; Warrier et al, 2004). It is therefore vital to investigate delivery vehicles that offer the ability to reduce tissue exposure to drug while dispensing an efficacious dose at the time of viral attack.…”

Section: Discussionmentioning

confidence: 99%

Enzymatic triggered release of an HIV-1 entry inhibitor from prostate specific antigen degradable microparticles

Clark¹,

Aliyar²,

Lee³

et al. 2011

International Journal of Pharmaceutics

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This paper describes the design, construction and characterization of the first anti-HIV drug delivery system that is triggered to release its contents in the presence of human semen. Microgel particles were synthesized with a crosslinker containing a peptide substrate for the seminal serine protease prostate specific antigen (PSA) and were loaded with the HIV-1 entry inhibitor sodium poly(styrene-4-sulfonate) (pSS). The particles were composed of N-2-hydroxyproplymethacrylamide and bis-methacrylamide functionalized peptides based on the PSA substrates GISSFYSSK and GISSQYSSK. Exposure to human seminal plasma (HSP) degraded the microgel network and triggered the release of the entrapped antiviral polymer. Particles with the crosslinker composed of the substrate GISSFYSSK showed 17 times faster degradation in seminal plasma than that of the crosslinker composed of GISSQYSSK. The microgel particles containing 1 mol% GISSFYSSK peptide crosslinker showed complete degradation in 30 hours in the presence of HSP at 37 °C and pSS released from the microgels within 30 minutes reached a concentration of 10 µg/mL, equivalent to the published IC90 for pSS. The released pSS inactivated HIV-1 in the presence of HSP. The solid phase synthesis of the crosslinkers, preparation of the particles by inverse microemulsion polymerization, HSP-triggered release of pSS and inactivation of HIV-1 studies are described.

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“…Cells were then exposed to the indicated concentrations of LC, CS, or DS for 1 h. Following the exposure period, cells were washed and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay [67,68] of viability at the indicated times after washout of the antiviral compounds. In assays involving PBMCs, cells were seeded at a density of 1 × 10 5 cells/well in a 96-well plate and subsequently exposed to LC, CS, or DS for 1 h. Following the exposure period, cells were washed and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay [69,70] of viability at the indicated times after washout. In both assays, viability following compound exposure was determined relative to mock-exposed cells.…”

Section: Methodsmentioning

confidence: 99%

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

Pirrone

Passic

Wigdahl

et al. 2012

Virol J

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BackgroundContinued efforts are being directed toward the development of microbicides that will be used to reduce or eliminate the risk of HIV-1 sexual transmission. Unfortunately, clinical trials involving polyanion-containing microbicide formulations, including Carraguard (λ-carrageenan [LC]) and Ushercell (cellulose sulfate [CS]) demonstrated that these products were ineffective and may have, in some circumstances, increased the risk of HIV-1 infection. These findings prompted reassessments of the in vitro activities of these agents to determine whether variables that can affect agent safety and efficacy had been overlooked during preclinical testing. One such variable is product retention and loss following topical application.ResultsIn the present studies involving an HIV-1-susceptible cell line and primary human immune cells, product loss was mimicked by introducing and then removing polyanionic compounds prior to HIV-1 infection. In these in vitro "washout" experiments, LC and CS significantly enhanced HIV-1 infection, despite potent antiviral activity when introduced simultaneously with the virus. The presence and magnitude of this effect were dependent on compound identity and concentration; target cell; interval between compound removal and virus challenge; and coreceptor usage. Levels of enhancement (relative to controls) were considerable, exceeding a 200% increase (CS) in P4-R5 MAGI cells and a 300% increase (LC) in human peripheral blood mononuclear cells.ConclusionsThese studies, which demonstrate significant increases in HIV-1 infection subsequent to application and removal of LC and CS, support plausible explanations for the failures of microbicides formulated from these compounds. Detailed studies are now underway to determine the mechanism responsible for this enhancement effect and to assess the potential contribution of this effect to the clinical failures of these agents.

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Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G

Cited by 14 publications

References 19 publications

Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety

Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety

Enzymatic triggered release of an HIV-1 entry inhibitor from prostate specific antigen degradable microparticles

Application and removal of polyanionic microbicide compounds enhances subsequent infection by HIV-1

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