Preclinical Testing of Candidate Topical Microbicides for Anti-Human Immunodeficiency Virus Type 1 Activity and Tissue Toxicity in a Human Cervical Explant Culture

Cummins, James E.; Guarner, Jeannette; Flowers, Lisa; Guenthner, Patricia C.; Bartlett, Jeanine; Morken, Timothy; Grohskopf, Lisa A.; Paxton, Lynn A.; Dezzutti, Charlene S.

doi:10.1128/aac.01129-06

Cited by 129 publications

(153 citation statements)

References 38 publications

Supporting

Mentioning

145

Contrasting

Unclassified

Order By: Relevance

“…To confirm the results obtained with the VEC-100 tissue, human ectocervical tissue was obtained after surgery and placed in culture using a polarized system (7,26). The HEC IQP-0528 gel and HEC placebo gel preserved tissue viability similarly to control (untreated) explants, as measured by the MTT assay (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Evaluations of the safety and antiviral activity of the lead formulation, IQP-0528, were performed as previously described (7,26). Briefly, the explant was placed in a transwell with the luminal side up.…”

Section: Methodsmentioning

confidence: 99%

“…To ensure an even spread of the gels and to allow them to be mixed with HIV-1 for the efficacy evaluation (below), a 1:5 dilution of IQP-0528 or HEC placebo gels was applied to the apical side of the explants for 18 h. Control explants were untreated or treated with an apically applied 1:5 dilution of 2% N-9 gel (Gynol II; purchased over the counter). The following day, the explants were washed and safety was evaluated by using an MTT [1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan] assay and histology methods (7,26).…”

Section: Methodsmentioning

confidence: 99%

“…We evaluated the safety and efficacy of the PYD gel formulation using reconstructed VEC-100 tissue (MatTek Corp.) and human polarized ectocervical tissue. The VEC-100 tissue recapitulates only the morphological characteristics of the stratified squamous epithelial layer, whereas the polarized ectocervical explants contains both epithelium and relevant immune cells (2,7,8,26). In an in vitro HIV-1 entry inhibition assay the 3.0% HEC gel with 0.25% IQP-0528 demonstrated a 50% effective concentration (EC 50 ) of 0.14 g/ml of gel in culture media, corresponding to ϳ0.001 M IQP-0528, and showed complete protection of the human polarized ectocervical tissue against HIV infection.…”

mentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…The product was tested for safety and efficacy in vitro in a cell-based model using HIV-1 IIIB (CXCR4 virus) (82) and an explant tissue-based model using HIV-1 BaL (CCR5 virus) (83). Human phase 1 studies for this product have shown that the product is safe to healthy women at low risk for HIV who were sexually abstinent (58), safe and acceptable in HIV-positive women who were sexually abstinent (84), and acceptable by both partners (85).…”

Section: Semisolids-hydrogelsmentioning

confidence: 99%

Vaginal Drug Delivery Systems for HIV Prevention

Rohan

Sassi

2009

AAPS J

141

130

View full text Add to dashboard Cite

Abstract. Microbicides have become a principal focus for HIV prevention strategies. The successful design of drug delivery systems for vaginal microbicide drug candidates brings with it a multitude of challenges. It is imperative that the chemical and physical characteristics of the drug candidate and its mechanism of action be clearly understood and considered to successfully deliver and target drug candidates efficiently. In addition, an understanding of the dynamic nature of the vaginal environment, the tissue and innate barriers present, as well as patient preferences are critical considerations in the design of effective microbicide products. Although the majority of drug candidates clinically evaluated to date have been delivered using conventional semisolid aqueous-based gel dosage forms, drug delivery system design has recently been extended to include advanced delivery systems such as vaginal rings, quick-dissolve films, and tablets. Ultimately, it may be necessary to develop multiple dosage platforms for a single active agent to provide users with options that can be used within the constraints of their social environment, personal choice, and environmental conditions.

show abstract

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

Hendrix

2018

Clin Pharma and Therapeutics

View full text Add to dashboard Cite

The US Food and Drug Administration (FDA) approved oral daily tenofovir/emtricitabine (Truvada) for pre-exposure prophylaxis of human immunodeficiency virus (HIV) infection in 2012 on the basis of two randomized controlled trials (RCTs), one in men who have sex with men (MSM) and another in HIV serodiscordant heterosexual couples. Subsequently, even greater efficacy has been demonstrated in MSM with rapid population-level incidence reductions in some locations. In contrast, studies of antiretroviral pre-exposure prophylaxis (PrEP) in heterosexual women showed only modest or no efficacy, largely attributed to low adherence. The mixed results of antiretroviral-based PrEP bear witness to unique drug development challenges at this complicated intersection of sexual behavior, public health, and drug development. Multiple innovative methods and formulation strategies followed to address unmet medical needs of persons struggling with daily oral PrEP adherence or preference for nonsystemic PrEP options. Clinical pharmacology plays essential roles throughout this PrEP development process, especially in early product development and through pharmacologically informed enhancement and interpretation of clinical trials.

show abstract

Preclinical Testing of Candidate Topical Microbicides for Anti-Human Immunodeficiency Virus Type 1 Activity and Tissue Toxicity in a Human Cervical Explant Culture

Cited by 129 publications

References 38 publications

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

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

Vaginal Drug Delivery Systems for HIV Prevention

HIV Antiretroviral Pre‐Exposure Prophylaxis: Development Challenges and Pipeline Promise

Contact Info

Product

Resources

About