This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In the only published study of acute toxicity of rectal microbicides, Phillips, et al., demonstrated that intrarectal administration of a nonoxynol-9 gel (2% N-9; K-Y Plus) is associated with shedding of sheets of rectal epithelium that can be observed in rectal lavage fluid after only 15 minutes of exposure. This study raised the concern that loss of the single layer of mucosal epithelium would result in exposure of the underlying lamina propria, perhaps facilitating additional drug toxicity and increasing the risk of HIV transmission. While the authors concluded that the effect on rectal epithelia was related to the gel's N-9 content, it is possible that some of the observed effect was secondary to a tonicity gradient between the topical gel and the colonic lumen. In our own lab we have measured the osmolality of K-Y Plus at 2038 mOsms/kg, while, in comparison, the osmolality of the colonic lumen is approximately 300 mOsms/kg. Others have shown that hyperosmolar and hypertonic insult to the colonic mucosa results in cell degeneration and sloughing of epithelia, net intraluminal fluid and mucus secretion, and altered permeability. Rectally-administered hyperosmolar solutions (Fleet's Enema ) also cause sloughing of the rectal epithelia. These insults to mucosal integrity may increase the risk for HIV transmission and show a temporal relationship between epithelial injury and exfoliation that are similar to the results obtained by Phillips. In our own pilot studies we have shown that adminisration of a hyperosmolar gel (K-Y Jelly) is associated with intraluminal volume expansion (persumably through colonic secretion of water). Based on this preliminary data and others' findings of hyperosmolar toxicity, we hypothesize that intrarectal administration of hyperosmolar gels generates an osmotic pressure gradient (hypertonicity) that results in acute epithelial injury temporally associated with intraluminal fluid secretion, including epithelial sloughing and, secondarily, increased colonic permeability. We propose to study the distribution and toxicity of both hyper- and iso-osmolar gels in healthy MSM. We will use flexible sigmoidoscopy with scintillation counting of brushings to assess level of exposure of the colonic lumen to our test vehicle, and biopsy and rectal washings will be obtained to determine histologic changes. Functional assessment of colonic permeability changes will be measured using rectal absorption of a small molecule radioisotope which is renally cleared and detectable in the urine. Understanding the effect of gel osmolality on gel distribution and toxicity of the gel in the distal colon is critical to developing topical HIV microbicides vehicles that cover the desired anatomy of the distal colon to prevent HIV infection without toxicity.
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