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Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

ABSTRACT: The exposure of oral antiretroviral (ARV) drugs in the female genital tract (FGT) is variable and almost unpredictable. Identifying an efficient method to find compounds with high tissue penetration would streamline the development of regimens for both HIV preexposure prophylaxis and viral reservoir targeting. Here we describe the cheminformatics investigation of diverse drugs with known FGT penetration using cluster analysis and quantitative structure-activity relationships (QSAR) modeling. A literature search over the 1950-2012 period identified 58 compounds (including 21 ARVs and representing 13 drug classes) associated with their actual concentration data for cervical or vaginal tissue, or cervicovaginal fluid. Cluster analysis revealed significant trends in the penetrative ability for certain chemotypes. QSAR models to predict genital tract concentrations normalized to blood plasma concentrations were developed with two machine learning techniques utilizing drugs' molecular descriptors and pharmacokinetic parameters as inputs. The QSAR model with the highest predictive accuracy had R(2)test=0.47. High volume of distribution, high MRP1 substrate probability, and low MRP4 substrate probability were associated with FGT concentrations ?1.5-fold plasma concentrations. However, due to the limited FGT data available, prediction performances of all models were low. Despite this limitation, we were able to support our findings by correctly predicting the penetration class of rilpivirine and dolutegravir. With more data to enrich the models, we believe these methods could potentially enhance the current approach of clinical testing.

SUBMITTER: Thompson CG

PROVIDER: S-EPMC4208595 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

Thompson Corbin G CG Sedykh Alexander A Nicol Melanie R MR Muratov Eugene E Fourches Denis D Tropsha Alexander A Kashuba Angela D M AD

AIDS research and human retroviruses 20140313 11

The exposure of oral antiretroviral (ARV) drugs in the female genital tract (FGT) is variable and almost unpredictable. Identifying an efficient method to find compounds with high tissue penetration would streamline the development of regimens for both HIV preexposure prophylaxis and viral reservoir targeting. Here we describe the cheminformatics investigation of diverse drugs with known FGT penetration using cluster analysis and quantitative structure-activity relationships (QSAR) modeling. A l ...[more]

PMID: 24512359

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Project description:ObjectiveTo examine the incidence of lower genital tract dysplasia in women after solid organ transplantation, to evaluate risk factors associated with development of dysplasia, and to assess the timeline of disease development.MethodsThis was a retrospective study of female patients who underwent solid organ transplantation at a large-volume tertiary care center between 2000 and 2015. Demographic and clinicopathologic factors were extracted from electronic medical records. Cumulative incidence of lower genital tract dysplasia was calculated, and univariate and multivariable logistic regression were performed to identify risk factors for the development of dysplasia.ResultsAmong 394 female solid organ transplant recipients, the median age was 41 years (interquartile range 29-53). Forty-seven (11.9%; 95% CI 8.8-15.9%) women developed lower genital tract dysplasia over a median follow-up of 7.8 years (interquartile range 4.6-12.9). Thirty-eight (9.6%) developed cervical intraepithelial neoplasia (CIN), with 14 (3.6%) diagnosed with CIN 2 or worse (one was cervical carcinoma). Nineteen (4.8%) developed noncervical lower genital tract dysplasia, including vulvar, vaginal, or anal dysplasia, with 13 (3.3%) diagnosed with high-grade dysplasia or worse (five were lower genital tract carcinoma [three anal, one vulvar, and one vaginal]). Ten (2.5%) developed both cervical and noncervical lower genital tract dysplasia. Black race was significantly associated with developing dysplasia (odds ratio [OR] 2.86; 95% CI 1.33-6.13) as was hydroxychloroquine use (OR 5.95; 95% CI 1.96-18.09). High-grade cervical dysplasia was diagnosed at a median interval of 3.18 years after transplant; noncervical high-grade lower genital tract dysplasia was diagnosed at a median interval of 3.94 years.ConclusionsOne in eight transplant recipients developed lower genital tract dysplasia and approximately half were high-grade dysplasia or cancer. Black race and hydroxychloroquine use were associated with an increased risk of dysplasia. Yearly cervical screening and comprehensive lower genital examination beyond the cervix is indicated in this population.

Project description:BACKGROUND: High concentrations of pro-inflammatory cytokines have been previously observed in the genital fluids of women enrolled in microbicide trials and may explain observed increased HIV transmission in some of these trials. Although the longitudinal nature of these studies allows within-subject comparisons of post-product levels to baseline levels, the fact that the physiologic variations of these cytokines and other markers of immune activation are not fully defined in different populations, makes it difficult to assess changes that can be directly attributed to microbicide use as opposed to other biological and behavioural factors. METHODS: Cervicovaginal lavage samples were collected from 30 healthy Caucasian and assayed for concentrations of ten cytokines/chemokines, total protein content and two antimicrobial proteins using a multiplex immunoassay and ELISA. Cellular markers were characterized by flow cytometry on mononuclear cells collected from the endocervix using flocked swabs. Bacterial quantification was performed using quantitative PCR. RESULTS: Ectopy, menstrual cycle phase, prostate-specific antigen and presence of leucocytes in endocervical cells' supernatant were associated with the concentrations of cyto-/chemokines in cervicovaginal secretions. Approximately 3% of endocervical cells collected were monocytes of which a median of 52% (SD ?= 17) expressed both CD4 and CCR5 markers. Approximately 1% of the total cells were T-cells with a median of 61% (SD ?= 10) CD4 and CCR5 expression. Around 5% of the monocytes and 16% of the T-cells expressed the immune activation marker HLA-DR. Higher percentages of T-cells were associated with greater quantities of IL-1RA, GM-CSF and elafin. CONCLUSION: We demonstrate the presence of selected soluble and cellular immune activation markers and identify their predictors in the female genital tract of healthy women. Future clinical trials should consider ectopy, sexual activity, menstrual cycle phase and presence of bacterial species as possible confounders when evaluating the possible inflammatory effects of microbicide compounds.

Dataset Information

Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

Publications

Short communication: cheminformatics analysis to identify predictors of antiviral drug penetration into the female genital tract.

Similar Datasets

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