Modulation of Cervicovaginal Drug Transporters and Tissue Distribution by Film-Released Tenofovir and Darunavir for Topical Prevention of HIV-1.

Clinical trials have demonstrated partial protection against HIV-1 infection by vaginal microbicide formulations based on antiretroviral (ARV) drugs. Improved formulations that will maintain sustained drug concentrations at viral target sites in the cervicovaginal mucosa are needed. We have previously demonstrated that treatment of cervicovaginal cell lines with ARV drugs can alter gene expression of drug transporters, suggesting that the mucosal disposition of ARV drugs delivered vaginally can be modulated by drug transporters.

Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial.

Background: An intravaginal ring that releases the tenofovir prodrug, tenofovir disoproxil fumarate, provided 100% protection in macaques against simian HIV and was safe in a 14-day clinical trial in sexually abstinent women. We aimed to assess the safety and pharmacokinetics of this intravaginal ring over 90 days in sexually active women.

Methods: We did a phase 1, single-blind, randomised, placebo-controlled trial to assess safety, pharmacokinetics, and acceptability of a tenofovir disoproxil fumarate intravaginal ring used continuously with monthly ring changes for 3 months.

Vaginal microbiome modulates topical antiretroviral drug pharmacokinetics.

Tenofovir gel and dapivirine ring provided variable HIV protection in clinical trials, reflecting poor adherence and possibly biological factors. We hypothesized that vaginal microbiota modulates pharmacokinetics and tested the effects of pH, individual bacteria, and vaginal swabs from women on pharmacokinetics and antiviral activity. Tenofovir, but not dapivirine, uptake by human cells was reduced as pH increased.

Differential Mechanisms of Tenofovir and Tenofovir Disoproxil Fumarate Cellular Transport and Implications for Topical Preexposure Prophylaxis.

Intravaginal rings releasing tenofovir (TFV) or its prodrug, tenofovir disoproxil fumarate (TDF), are being evaluated for HIV and herpes simplex virus (HSV) prevention. The current studies were designed to determine the mechanisms of drug accumulation in human vaginal and immune cells. The exposure of vaginal epithelial or T cells to equimolar concentrations of radiolabeled TDF resulted in over 10-fold higher intracellular drug levels than exposure to TFV.

A phase 1 randomized placebo-controlled safety and pharmacokinetic trial of a tenofovir disoproxil fumarate vaginal ring.

Background: Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir (TFV), may be ideal for topical HIV preexposure prophylaxis because it has higher tissue and cell permeability than TFV; is not adversely impacted by seminal proteins; and its active metabolite, TFV-diphosphate (TFV-DP), has a long intracellular half-life. We engineered a TDF eluting polyurethane reservoir intravaginal ring (IVR) to provide near constant mucosal antiretroviral concentrations.

Methods: A first-in-human randomized placebo-controlled trial was conducted to assess the safety and pharmacokinetics of the TDF IVR in healthy, sexually abstinent women (15 TDF and 15 placebo).

Drug transporter gene expression in human colorectal tissue and cell lines: modulation with antiretrovirals for microbicide optimization.

Objectives: The objectives of this study were to comprehensively assess mRNA expression of 84 drug transporters in human colorectal biopsies and six representative cell lines, and to investigate the alteration of drug transporter gene expression after exposure to three candidate microbicidal antiretroviral (ARV) drugs (tenofovir, darunavir and dapivirine) in the colorectal epithelium. The outcome of the objectives informs development of optimal ARV-based microbicidal formulations for prevention of HIV-1 infection.

Methods: Drug transporter mRNA expression was quantified from colorectal biopsies and cell lines by quantitative real-time PCR.

A protein caught in a kinetic trap: structures and stabilities of insulin disulfide isomers.

Proinsulin contains six cysteines whose specific pairing (A6-A11, A7-B7, and A20-B19) is a defining feature of the insulin fold. Pairing information is contained within A and B domains as demonstrated by studies of insulin chain recombination. Two insulin isomers containing non-native disulfide bridges ([A7-A11,A6-B7,A20-B19] and [A6-A7,A11-B7,A20-B19]), previously prepared by directed chemical synthesis, are metastable and biologically active.

A decision tree for tuberculosis contact investigation.

The University of Alabama at Birmingham and the Alabama Department of Public Health recently developed a logistic regression model showing those variables that are most likely to predict a positive tuberculin skin test in contacts of tuberculosis cases. However, translating such a model into field application requires a stepwise approach. This article describes a decision tree developed to assist public health workers in determining which contacts are most likely to have a positive tuberculin skin test.

Mode of action of RNA/DNA oligonucleotides: progress in the development of gene repair as a therapy for alpha(1)-antitrypsin deficiency.

We describe a technology developed for the site-specific correction of a single base carried on an episome or chromosome in prokaryotic and eukaryotic cells. Critical to the development of this technology as a therapeutic device for treating genetic disorders, like alpha(1)-antitrypsin deficiency, is the establishment of a standardized assay to study its mode of action and structure-activity relationships (SARs). To this end, a positive-selection system in Escherichia coli has been developed to assess RNA/DNA oligonucleotide (RDO)-directed repair activity.

Predictive model to identify positive tuberculosis skin test results during contact investigations.

Context: Budgetary constraints in tuberculosis (TB) control programs require streamlining contact investigations without sacrificing disease control.

Objective: To develop more efficient methods of TB contact investigation by creating a model of TB transmission using variables that best predict a positive tuberculin skin test among contacts of an active TB case.

Design, Setting, And Subjects: After standardizing the interview and documentation process, data were collected on 292 consecutive TB cases and their 2941 contacts identified by the Alabama Department of Public Health between January and October 1998.