Isoosmolar enemas demonstrate preferential gastrointestinal distribution, safety, and acceptability compared with hyperosmolar and hypoosmolar enemas as a potential delivery vehicle for rectal microbicides

Abstract

Rectally applied antiretroviral microbicides for preexposure prophylaxis (PrEP) of HIV infection are currently in development. Since enemas (rectal douches) are commonly used by men who have sex with men prior to receptive anal intercourse, a microbicide enema could enhance PrEP adherence by fitting seamlessly within the usual sexual practices. We assessed the distribution, safety, and acceptability of three enema types-hyperosmolar (Fleet), hypoosmolar (distilled water), and isoosmolar (Normosol-R)-in a crossover design. Nine men received each enema type in random order. Enemas were radiolabeled [(99m)Tc-diethylene triamine pentaacetic acid (DTPA)] to assess enema distribution in the colon using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Plasma (99m)Tc-DTPA indicated mucosal permeability. Sigmoidoscopic colon tissue biopsies were taken to assess injury as well as tissue penetration of the (99m)Tc-DTPA. Acceptability was assessed after each product use and at the end of the study. SPECT/CT imaging showed that the isoosmolar enema had greater proximal colonic distribution (up to the splenic flexure) and greater luminal and colon tissue concentrations of (99m)Tc-DTPA when compared to the other enemas (p<0.01). Colon biopsies also showed that only the hyperosmolar enema caused sloughing of the colonic epithelium (p<0.05). In permeability testing, the hypoosmolar enema had higher plasma (99m)Tc-DTPA 24-h area under the concentration-time curve and peak concentration compared to the hyperosmolar and isoosmolar enemas, respectively. Acceptability was generally good with no clear preferences among the three enema types. The isoosmolar enema was superior or similar to the other enemas in all categories and is a good candidate for further development as a rectal microbicide vehicle.

FIG. 1.

Single photon emission computed tomography/computed tomography (SPECT/CT) imaging of a research participant 2 h following intrarectal dosing with each enema. The first and second row from the top show the coronal and left sagittal view of SPECT/CT, respectively. The CT image is in grayscale indicating bone and soft tissue. The SPECT image of the ^99mTc-diethylene triamine pentaacetic acid (DTPA) signal is superimposed in color scale from high (yellow) to low (blue) intensity. [Note: this fused image includes only one sagittal plane (slice) that has the greatest intensity.] The third row shows SPECT maximal intensity projections (MIP) of ^99mTc-DTPA activity in grayscale corresponding to the left sagittal view in the second row. [Note: The MIP images show the greatest signal intensity from among all sagittal planes (slices) projected onto a two-dimensional sagittal image. The MIP shows the full distribution more fully because it includes all, not only one sagittal plane, unlike the fused SPECT/CT images.] The isoosmolar enema (left panels) shows radiolabel throughout the rectum, sigmoid, and descending colon. The hyperosmolar and hypoosmolar enemas show distribution limited to the rectosigmoid and lower in intensity indicated by the upscaled background intensity.