A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring

Weisberg, Edith; Fraser, Ian S.; Baker, Jay M.; Archer, David F.; Bm, Landgren; Killick, S.R.; Soutter, Pat; Krause, T; d’Arcangues, Catherine

doi:10.1016/s0010-7824(00)00137-2

Cited by 23 publications

(15 citation statements)

References 12 publications

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“…Bounds et al studied an early version of the hormone replacement therapy ring Femring that had remarkable mechanical stiffness, and it was concluded that the ring contributed to the creation of ulcerative lesions in the vagina (5). Subsequently, several large clinical safety studies have evaluated an array of medicated and nonmedicated IVRs composed of silicone and ethylene vinyl acetate polymers comprising various dimensions and varied ring stiffness (14,27,41,43,47,59). None of these studies found a significant ring contribution in creating epithelial lesions and/or altering vaginal microflora when tested for up to 1 year.…”

Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Johnson

Clark

Albright

et al. 2012

Antimicrob Agents Chemother

117

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A vaginal gel containing the antiretroviral tenofovir (TFV) recently demonstrated 39% protection against HIV infection in women. We designed and evaluated a novel reservoir TFV intravaginal ring (IVR) to potentially improve product effectiveness by providing a more controlled and sustained vaginal dose to maintain cervicovaginal concentrations. Polyurethane tubing of various hydrophilicities was filled with a high-density TFV/glycerol/water semisolid paste and then end-sealed to create IVRs. In vitro, TFV release increased with polyurethane hydrophilicity, with 35 weight percent water-swelling polyurethane IVRs achieving an approximately 10-mg/day release for 90 days with mechanical stiffness similar to that of the commercially available NuvaRing. This design was evaluated in two 90-day in vivo sheep studies for TFV pharmacokinetics and safety. Overall, TFV vaginal tissue, vaginal fluid, and plasma levels were relatively time independent over the 90-day duration at approximately 10 4 ng/g, 10 6 ng/g, and 10 1 ng/ml, respectively, near or exceeding the highest observed concentrations in a TFV 1% gel control group. TFV vaginal fluid concentrations were approximately 1,000-fold greater than levels shown to provide significant protection in women using the TFV 1% gel. There were no toxicological findings following placebo and TFV IVR treatment for 28 or 90 days, although slight to moderate increases in inflammatory infiltrates in the vaginal epithelia were observed in these animals compared to naïve animals. In summary, the controlled release of TFV from this reservoir IVR provided elevated sheep vaginal concentrations for 90 days to merit its further evaluation as an HIV prophylactic. R ecent progress in antiretroviral HIV prevention research has advanced the field from concept toward medical practice (46). The CAPRISA 004 study demonstrated that a vaginal gel containing the reverse transcriptase inhibitor tenofovir (TFV) was partially effective in preventing HIV transmission in women (1), with significant protection observed in women who maintained preventative TFV concentrations of at least 1,000 ng/ml in vaginal fluid (23). However, the overall effectiveness (39%) was likely reduced by poor user adherence to the inconvenient before-andafter-sex dosing regimen. The correlation of adherence and TFV vaginal fluid concentrations to protection was a key finding (23,24), indicating the need for vaginal drug delivery systems that attain and maintain elevated user adherence and vaginal drug concentrations. More recently, the VOICE trial tested the same TFV 1% gel formulation as CAPRISA 004 but with a once-daily dosage regimen and failed to show any effectiveness in women. Here, as well, low adherence may have contributed to the gel's inability to prevent HIV transmission (54). As a result, we (6, 21) and others (4,35,36,44,49) aim to develop TFV drug delivery systems to provide sustained protective vaginal tissue concentrations and potentially increase user adherence.The micromolar anti-HIV activity of TFV motivated sel...

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Section: Fig 7 Proximal and Distal Tfv Vaginal Tissue Concentrations mentioning

confidence: 99%

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Johnson

Clark

Albright

et al. 2012

Antimicrob Agents Chemother

117

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“…IVRs with 5.0 mm XD and 21% TFV loading had F 10 values more than twice those of NuvaRing® prior to release testing and had F 10 values approximately 30% less than NuvaRing® after release testing. Various reports from clinical literature [20][21][22] indicate an optimal range exists for IVR mechanical properties, however, there is no consensus as to the appropriate metric for quantitatively determining mechanical IVR acceptability. If the load under compression is insufficient, an IVR may be displaced or expelled by the user.…”

Section: Ivr Mechanical Characterizationmentioning

confidence: 99%

“…Excessively inflexible IVRs may cause user discomfort or epithelial barrier damage, while excessively compressible IVRs may be expelled during use [20][21][22]. These problems are compounded in swellable systems as polymer properties will likely vary during swelling and drug dissolution.…”

Section: Introductionmentioning

confidence: 99%

Quantitative evaluation of a hydrophilic matrix intravaginal ring for the sustained delivery of tenofovir

Clark

Johnson

Clark

et al. 2012

Journal of Controlled Release

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“…While high stiffness of an IVR could lead to difficulty in insertion and potential damage to the vaginal tissue post-application [37,38], low stiffness will result in lack of retention and difficulty in insertion [39]. Therefore, a relevant technique to evaluate mechanical performance is to measure the force required to compress the ring and/or the retractive forces exerted by a compressed ring.…”

Section: Methodsmentioning

confidence: 99%

Engineering a degradable polyurethane intravaginal ring for sustained delivery of dapivirine

Kaur

Gupta

Poursaid

et al. 2011

Drug Deliv. and Transl. Res.

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We describe the engineering of a degradable intravaginal ring (IVR) for the delivery of the potent HIV-1 reverse transcriptase inhibitor dapivirine. The degradable polymer used in fabricating the device incorporated poly(caprolactone) ester blocks in a poly(tetramethylene ether) glycol ABA type polyurethane backbone. The polymer was designed to maintain its structure for 1 month during usage and then degrade in the environment post-disposal. In vitro release of dapivirine showed zero-order kinetics for up to 1 month and significant levels of drug release into engineered vaginal tissue. The mechanical properties of the degradable IVR were comparable to those of a widely used contraceptive intravaginal ring upon exposure to simulated vaginal conditions. Incubation under simulated vaginal conditions for a month caused minimal degradation with minimal effect on the mechanical properties of the ring and polymer. The cytotoxicity evaluation of the drug-loaded IVRs against Vk2/E6E7 human vaginal epithelial cells, Lactobacillus jensenii, and engineered vaginal tissue constructs showed the degradable polyurethane to be non-toxic. In vitro evaluation of inflammatory potential monitored through the levels of inflammatory cytokines IL-8, IL-1α, IL-6, IL-1β, and MIP-3α when engineered EpiVaginal™ tissue was incubated with the polyurethanes suggested that the degradable polyurethane was comparable to commercial medical grade polyurethane. These results are encouraging for further development of this degradable IVR for topical vaginal delivery of microbicides.

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A randomized comparison of the effects on vaginal and cervical epithelium of a placebo vaginal ring with non-use of a ring

Cited by 23 publications

References 12 publications

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

A 90-Day Tenofovir Reservoir Intravaginal Ring for Mucosal HIV Prophylaxis

Quantitative evaluation of a hydrophilic matrix intravaginal ring for the sustained delivery of tenofovir

Engineering a degradable polyurethane intravaginal ring for sustained delivery of dapivirine

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