Vaginal microbicides: detecting toxicities in vivothat paradoxically increase pathogen transmission

Cone, Richard A.; Hoen, Timothy E.; Wong, XiXi; Abusuwwa, Raed; Anderson, Deborah J.; Moench, Thomas R.

doi:10.1186/1471-2334-6-90

Cited by 126 publications

(148 citation statements)

References 51 publications

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“…Numerous vaginal microbicides that have been tested in humans possess strong surfactant properties and, therefore, may also alter mucus pore size. However, most of these agents caused substantial toxicity to the vaginal epithelium by damaging cell membranes, and therefore failed to reduce (or in some cases even increased) infection rates (42)(43)(44)(45). Thus, whereas our results suggest that the use of surface-active agents may help limit infection by decreasing the flux of pathogens to the epithelium, this hypothesis can only be tested with agents that do not simultaneously compromise the epithelial cell layer.…”

Section: Discussionmentioning

confidence: 54%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

333

343

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The mechanisms by which mucus helps prevent viruses from infecting mucosal surfaces are not well understood. We engineered non-mucoadhesive nanoparticles of various sizes and used them as probes to determine the spacing between mucin fibers (pore sizes) in fresh undiluted human cervicovaginal mucus (CVM) obtained from volunteers with healthy vaginal microflora. We found that most pores in CVM have diameters significantly larger than human viruses (average pore size 340 ± 70 nm; range approximately 50–1800 nm). This mesh structure is substantially more open than the 15–100-nm spacing expected assuming mucus consists primarily of a random array of individual mucin fibers. Addition of a nonionic detergent to CVM caused the average pore size to decrease to 130 ± 50 nm. This suggests hydrophobic interactions between lipid-coated “naked” protein regions on mucins normally cause mucin fibers to self-condense and/or bundle with other fibers, creating mucin “cables” at least three times thicker than individual mucin fibers. Although the native mesh structure is not tight enough to trap most viruses, we found that herpes simplex virus (approximately 180 nm) was strongly trapped in CVM, moving at least 8,000-fold slower than non-mucoadhesive 200-nm nanoparticles. This work provides an accurate measurement of the pore structure of fresh, hydrated ex vivo CVM and demonstrates that mucoadhesion, rather than steric obstruction, may be a critical protective mechanism against a major sexually transmitted virus and perhaps other viruses.

show abstract

Section: Discussionmentioning

confidence: 54%

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Lai

Wang²,

Hida³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

333

343

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“…Thorough investigation of the toxicity and irritation potential of microbicide formulations is critical, since in the past some microbicides that have caused irritation to genital tissue also led to higher infection rates in women compared to placebos (2,6). VEC-100 tissue treated with an IQP-0528 HEC gel formulation showed no significant induction of cytokines or chemokines (Student t test, P Ͼ 0.05), suggesting the absence of any significant inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

“…We also evaluated the in vitro antiviral activity of the 3.0% HEC formulation using a luminescence assay as described previously (6). The HEC placebo gel was used as a negative control and Chicago sky blue was used as a positive control.…”

Section: Methodsmentioning

confidence: 99%

“…In addition to careful selection of the drug delivery vehicle and the active ingredient, a detailed exploration of the safety and efficacy of the end formulation is critical to the development of a microbicide. Particularly after the clinical failures of cellulose sulfate, N-9, Savvy, and several other microbicides, in vitro safety and efficacy evaluations have become a major component of topical microbicide product development (6,16,24). These studies offer a cost-effective method of evaluating microbicide formulations prior to more complex and expensive in vivo studies (36).…”

mentioning

confidence: 99%

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Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Mahalingam

Simmons

Ugaonkar

et al. 2011

Antimicrob Agents Chemother

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Pyrimidinediones, a novel class of compounds, have previously been shown to possess antiviral activity at nanomolar concentrations. One member of this class of compounds, IQP-0528, was selected as the lead molecule for formulation development owing to its stability at physiologically relevant conditions, wide therapeutic window, and antiviral activity in the nanomolar range. Here, we report the development of two vaginal gels-3.0% hydroxyethyl cellulose (HEC) formulation and a 0.65% Carbopol formulation-for the sustained delivery of IQP-0528. Stability studies under accelerated conditions confirmed the chemical stability of IQP-0528 and mechanical stability of the gel formulation for 3 months. In vitro release studies revealed that diffusion-controlled release of IQP-0528 occurred over 6 h, with an initial lag time of approximately 1 h. Based on the drug release profile, the 3.0% HEC gel was selected as the lead formulation for safety and activity evaluations. The in vitro and ex vivo safety evaluations showed no significant loss in cell viability or significant inflammatory response after treatment with a 3.0% HEC gel containing 0.25% IQP-0528. In an in vitro HIV-1 entry inhibition assay, the lead formulation showed an 50% effective concentration of 0.14 g/ml for gel in culture media, which corresponds to ϳ0.001 M IQP-0528. The antiviral activity was further confirmed by using polarized cervical explants, in which the formulation showed complete protection against HIV infection. In summary, these results are encouraging and warrant further evaluation of IQP-0528 gel formulations in in vivo models, as well as the development of alternative formulations for the delivery of IQP-0528 as a microbicide.

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“…8 Subsequent studies found that nonoxynol-9 and other detergent spermicides have toxic effects on vaginal mucosa (but the acidic spermicide, Buffergel, does not). 9 These concerns have led to advice that women at high risk of HIV infection should avoid using diaphragms. 10 It would be a pity if the renewed interest in the diaphragm now declines because of the lack of evidence of protective efficacy against HIV.…”

mentioning

confidence: 99%

Adding to the menu of modern methods - the diaphragm

Holmes

2010

Sex. Health

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Vaginal microbicides: detecting toxicities in vivothat paradoxically increase pathogen transmission

Cited by 126 publications

References 51 publications

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Nanoparticles reveal that human cervicovaginal mucus is riddled with pores larger than viruses

Vaginal Microbicide Gel for Delivery of IQP-0528, a Pyrimidinedione Analog with a Dual Mechanism of Action against HIV-1

Adding to the menu of modern methods - the diaphragm

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