Quantitative Imaging and Sigmoidoscopy to Assess Distribution of Rectal Microbicide Surrogates

Abstract

Understanding the distribution of microbicide and human immunodeficiency virus (HIV) within the gastrointestinal tract is critical to development of rectal HIV microbicides. A hydroxyethylcellulose-based microbicide surrogate or viscosity-matched semen surrogate, labeled with gadolinium-DTPA (diethylene triamine pentaacetic acid) and 99mTechnetium-sulfur colloid, was administered to three subjects under varying experimental conditions to evaluate effects of enema, coital simulation, and microbicide or semen simulant over 5 h duration. Quantitative assessment used single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI) imaging, and sigmoidoscopic sampling. Over 4 h, radiolabel migrated cephalad in all studies by a median (interquartile range) of 50% (29-102%; P<0.001), as far as the splenic flexure (approximately 60 cm) in 12% of studies. There was a correlation in concentration profile between endoscopic sampling and SPECT assessments. HIV-sized particles migrate retrograde, 60 cm in some studies, 4 h after simulated ejaculation in our model. SPECT/CT, MRI, and endoscopy can be used quantitatively to facilitate rational development of microbicides for rectal use.

Quantification of the spatial distribution of rectally applied surrogates for microbicide and semen in colon with SPECT and magnetic resonance imaging

“…Overall, the concentration-distance curves obtained with SPECT/CT and sigmoidoscopy appeared roughly similar as observed previously with an earlier SPECT concentration-distance estimation method [9]. However, the details of the distance-concentration curves developed by SPECT and sigmoidoscopy are clearly different as may be expected.…”

“…SPECT/CT imaging was performed as previously described [9] with a dual-head VG series system (GE Medical Systems, Waukesha, WI, USA) equipped with a low-end CT unit (Hawkeye). Summarizing, SPECT and CT images were reconstructed using filtered back projection with ordered subset expectation maximization (OSEM) into a 128 ¥ 128 matrix size and fused in the General Electric eNTEGRA workstation (version 1.04, GE Medical Systems, Waukesha, WI, USA).…”

“…We recently demonstrated the feasibility of describing drug distribution in the distal colon using non-invasive imaging with single photon emission computed tomography (SPECT)/computed tomography (CT) and magnetic resonance imaging (MRI), and invasive colon biopsies [9]. We wanted to develop more refined quantitative methods to summarize colonic drug distribution in an effort to provide pharmacokinetic parameter estimates to describe drug behaviour in this anatomical compartment.…”

Simultaneous Evaluation of Safety, Acceptability, Pericoital Kinetics, and Ex Vivo Pharmacodynamics Comparing Four Rectal Microbicide Vehicle Candidates

“…Coital simulation and HIV surrogate preparations were performed as previously described. 19,20,[22][23][24][25] All research participants were also given a dose of each study product for dosing at home in the context of RAI with a partner. The study products were partially blinded because investigators preparing the radiolabeled study product could discern subtle differences in the products.…”

“…Participants were imaged 2, 4, and 24 h after study product dosing (Phase A and B) using a dual-head Millennium VH SPECT/CT system (GE Medical Systems, Waukesha, WI) equipped with a low-dose computed tomography (CT) unit (Hawkeye) as previously described. 20,24,26 CT images were fused with attenuation corrected SPECT images using the General Electric eN-TEGRA nuclear medicine workstation, version 1.04 (GE Medical Systems, Waukesha, WI).…”