Quantitative assessment of altered rectal mucosal permeability due to rectally applied nonoxynol-9, biopsy, and simulated intercourse

Abstract

Background: Microbicide toxicity may reduce the efficacy of topical preexposure prophylaxis for human immunodeficiency virus (HIV) transmission. Noninvasive quantitative measures of microbicide toxicity would usefully inform microbicide development.

Methods: Ten subjects received 3 one-time interventions: 5 mL of Normosol-R fluid alone (negative control), 5 mL of 2% nonoxynol-9 (N-9) gel, and 5 mL of Normosol-R with coital simulation and sigmoidoscopic biopsy (CS + BX). Each dose of N-9 and Normosol-R contained 500 µCi of (99m)technetium-diethylene triamine pentaacetic acid. Plasma and urine radioactivity was assessed over 24 hours.

Results: The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was 12.0 times (95% confidence interval [CI], 6.8-21.0) and 8.4 times (95% CI, 5.2-13.5) the mean concentration after Normosol-R control receipt and CS + BX receipt, respectively; paired differences persisted for 24 hours. After N-9 dosing, the urine isotope level was 3.6 times (95% CI, 1.1-11.4) the level observed 8 hours after Normosol-R control receipt and 4.0 times (95% CI, 1.4-11.4) the level observed 4 hours after CS + BX receipt. Permeability after CS + BX receipt was greater than that after Normosol-R control receipt in 0-2-hour urine specimens only (mean permeability, 2.4; 95% CI, 1.0-5.8) but was not greater in blood.

Conclusions: Plasma sampling after rectal radioisotope administration provided quantitative estimates of altered mucosal permeability after chemical and mechanical stresses. Permeability testing may provide a useful noninvasive adjunct to assess the mucosal effects of candidate microbicides. Clinical Trials Registration. NCT00389311.

Figure 1.

Plasma ^99mtechnetium (^99mTc) level over time following a rectal dose with Normosol-R plus coital simulation and sigmoidoscopic biopsy (CS + BX), 2% nonoxynol-9 gel, and Normosol-R fluid alone (negative control). The y-axis denotes ^99mTc disintegrations per minute (DPM) adjusted (ie, divided) by the dose retained. Circles and triangles denote mean values, and whiskers denote 95% confidence intervals.

Figure 2.

Cumulative fraction of ^99mtechnetium (^99mTc) measured in urine following isotope injection, relative to the dose administered rectally. Time points represent the total activity measured for the urine collection interval. Circles and triangles denote mean values, and whiskers denote 95% confidence intervals (CIs). Values for Normosol-R fluid alone (negative control) and Normosol-R plus coital simulation and biopsy (CS + BX) are offset slightly from the actual time point so that CIs appear distinct for each study intervention.