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Edward J. Fuchs, Lisa A. Grohskopf, Linda A. Lee, Rahul P. Bakshi, Craig W. 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. Plasma and urine radioactivity was assessed over 24 hours.

The plasma radioisotope concentration peaked 1 hour after N-9 dosing. The mean maximum radioisotope concentration after N-9 receipt was After N-9 dosing, the urine isotope level was 3. 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.

Altered rectal perception is a biological marker of patients with irritable bowel syndrome

Vaginal microbicides in development should also be evaluated for rectal safety if not efficacysince it is probable that any HIV microbicide developed for vaginal use will be used rectally. Experience from the COL trial, a large-scale vaginal microbicide trial using nonoxynol-9 N-9demonstrates that the failure to fully understand the potential local toxicities of an Ältere anal microbicide formulation can impact efficacy and result in an increased risk of HIV transmission [ 3 ]. N-9 had been shown to cause mucosal erosions in the vagina and rectum, which has been postulated as a partial explanation for the increased HIV transmission rate in the COL study [ 4—8 ].

A large-scale trial of vaginally applied cellulose sulfate was halted when interim analysis indicated a higher HIV infection rate in the treatment group although subsequent statistical analysis did not demonstrate the same degree of ificance as the interim analysis [ 9 ]. In vitro studies indicate that cellulose sulfate may disrupt cellular junctions in the mucosal epithelium, facilitating HIV translocation across the epithelium [ 10 ].

The possible role of microbicide-induced mucosal toxicity highlights the need to understand the potential for toxicity early in microbicide development. To facilitate microbicide development, a simple, noninvasive, quantitative measure of altered colonic mucosal integrity is needed to assess the potential for altered mucosal integrity.

Challenges to mucosal integrity may result during clinical studies, either from chemical stress due to the microbicide product vehicle or active ingredientphysical stress sigmoidoscopic biopsyor sexual intercourse. These stresses may occur in microbicide development studies and have the potential to confound safety assessments. These changes may occur in the absence of visible mucosal damage, although erosions are also seen. Phillips et al have demonstrated that rectal administration of Ältere anal is associated with shedding of sheets of epithelia the single layer of cells lining the rectal mucosal surface 15 minutes after dosing, possibly increasing the likelihood of HIV transmission [ 1213 ].

Epithelial repair from a single dose of N-9 also occurs rapidly, with an intact epithelial barrier observed 2 hours after N-9 administration and an epithelial appearance indistinguishable from baseline by 8 hours after administration. Sigmoidoscopic sampling of the colonic mucosa, with or without simulated coital activity, may be performed during microbicide development to understand the pharmacokinetics or toxicity of ältere anal candidate microbicide or vehicle.

Even without the trauma of endoscopic biopsies, endoscopy has been observed to occasionally induce submucosal bruising, with elevation of the mucosal layer and submucosal hemorrhage.

Furthermore, the shearing and compressive forces associated with rectal intercourse might alter the epithelial layer. During rectal microbicide development, it is essential to understand whether such procedures or coital shearing stress may adversely affect the rectum by altering mucosal permeability, so that one can appropriately interpret the effects of topical microbicides on the mucosal lining of the distal colon.

Altered permeability is commonly tested by measuring the differential intestinal absorption of solutes of varying molecular weight [ 15—20 ]. These tests have been used primarily to evaluate small intestine permeability after oral administration of the test agent, but they have not been used to assess permeability in the rectum, where absorption is very low. A few reports involving comparisons of healthy volunteers with individuals with inflammatory bowel disease or other conditions with altered intestinal permeability suggest that radioisotope chelates administered intrarectally can distinguish differences in distal colon permeability [ 20—24 ].

We sought to determine whether a small radiolabeled molecule, 99m technetium—diethylene triamine pentaacetic acid 99m Tc-DTPAcan be used as a noninvasive measure of colonic mucosal permeability induced either by a known toxin, N-9, or by a combination of coital simulation and flexible sigmoidoscopy with multiple biopsies. We hypothesized that mucosal damage is measurable by simple tests of altered rectal permeability, ältere anal due to inflammatory changes or the physical disruption ältere anal the mucosal barrier, both of which occur after N-9 administration, or due to the physical trauma of coital forces and colonic biopsy.


After institutional review board approval was obtained, 10 MSM provided informed consent, were screened, and were enrolled in the study. All subjects agreed to refrain from receptive anal intercourse for 48 hours prior to and following each admission. The following day, ältere anal received a mL tap water enema 8 hours prior to dosing.

The preparative enema had a type and volume reported to be commonly used prior to receptive anal intercourse and was administered 8 hours prior to dosing, to minimize trauma to the colonic epithelium that would be evident at the time of vehicle dosing [ 13142526 ].

Supporting information

Subjects expelled the enema immediately after administration. On day 1, 2 hours prior to dosing, subjects were restricted to receive nothing by mouth. Subjects voided urine to empty the bladder just before dosing. All urine output was collected in separate containers at intervals of 0—2, 2—4, 4—8, 8—12, and 12—24 hours after dosing, and 1-mL aliquots were taken for gamma counting. Subjects were asked to void completely at the end of each interval; the time of their last void in the interval defined the end of that interval.

Blood samples were obtained by venipuncture at the midpoint of each timed urine collection ie, 1, 3, 6, 10, and 18 hours after dosing. Blood samples were immediately centrifuged, and 1-mL plasma aliquots were collected for gamma counting. Two hours after vehicle dosing, subjects d a regular diet. After the hour urine collection was completed, subjects continued to phase 2. The time of any bowel movement occurring during the study admission was recorded.

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Subjects remained confined to the ältere anal, to allow a 2-day rest period between isotope dosing during phase 1 and initiation of phase 2. The evening prior to dosing, subjects were placed on the same dietary restrictions and underwent the same bowel preparation as described above. Within 10 minutes prior to dosing, a single tube of blood was obtained by venipuncture, and subjects were instructed to void as completely as possible to provide urine to confirm by gamma counting that no residual gamma activity remained in the urine.

Urine and plasma samples were collected and evaluated as described above. Subjects d a regular diet 2 hours after dosing.

Subjects were discharged home once the hour urine collection interval was completed. Just prior to discharge, subjects were counseled to refrain from receptive anal intercourse for 48 hours following discharge and for 48 hours preceding the next study admission. Condom use for insertive partners was strongly advised. Subjects were admitted to the clinical research unit once more and placed on the same restricted diet and underwent the same bowel preparation as described for prior phases. The following morning, subjects were taken to the endoscopy suite.

The dilator was then removed by the subject. Flexible sigmoidoscopy was then performed by the study gastroenterologist L. Biopsy forceps Microvasive ; Boston Scientific, Natick, MA were passed through the endoscope port, and 20 pinch biopsy specimens were obtained 8—25 cm beyond the anal verge.

Ältere anal remained supine until completion of isotope dosing and were then allowed to ambulate freely. Timed collection of urine and plasma specimens, resumption of regular diet, recording of bowel movements, and discharge counseling were performed as described above for phase 2. The test vehicles were compounded with radioisotope and loaded into dosing syringes by a commercial radiopharmacy Cardinal Health, Beltsville, MD and delivered to the nuclear medicine facility at The Johns Hopkins Hospital. Subjects were placed in supine position, and the compounded isotope vehicle was injected intrarectally, using a lightly lubricated Luer applicator product ; Professional Compounding Centers of America, Houston, TX.

Following dosing, the residual radioactivity in each syringe was measured. This amount was decay corrected and subtracted from the initial syringe measurement, to determine the total dose administered to the subject. Samples were corrected for background activity and instrument detector efficiency. To determine the cumulative urine gamma activity for a specified interval, gamma counts for urine aliquots were ältere anal for urine volume and sampling interval duration.

Plasma and urine were then decay corrected to for time elapsed and were divided by the total amount of activity administered, to normalize for the dose retained by each subject. Plasma and urine are expressed as a fraction of the initially administered isotope dose.

The peak isotope concentration and time to peak concentration were assessed by visual inspection.

Areas under the curve were calculated using the linear trapezoidal rule. For statistical analyses, subjects served as their own controls. Comparisons between vehicle interventions were made for plasma and urine mucosal permeability isotope concentrations by using paired t testing of log-transformed data SPSS; IBM, Somers, NY. Ten MSM were enrolled and completed the study. Nine subjects ältere anal HIV seropositive, but they were otherwise healthy. All subjects tolerated the study procedures well. The mean time to first stool following dosing was 2.

To control for these timing and dose-retention differences, all permeability calculations were made with radioisotope decay correction and dose-adjusted measurements. Following the test dose for all 3 conditions, the measurable radioisotope level increased in blood and urine before falling back toward background gamma activity Figures 1 and 2.

The radioisotope level in plasma, expressed as a fraction of the dose administered, peaked at the first observation time 1 hour following N-9 dosing and declined thereafter. Urine radioisotope levels demonstrated a similar pattern, with higher and earlier peak levels detected in the 0—2-hour ältere anal following N-9 dosing, compared with the other 2 test conditions, for which levels peaked in 2—4-hour specimens.

The y -axis denotes 99m Tc disintegrations per minute DPM adjusted ie, divided by the dose retained. Cumulative fraction of 99m technetium 99m Tc measured in urine following isotope injection, relative to the dose administered rectally. Time points represent the total activity measured for the urine collection interval. The mean cumulative fraction of the administered dose detected in urine was higher for the N-9 intervention at 6. Aliquots from the urine collections showed that the mean radioisotope level after the N-9 intervention was The difference in permeability was most pronounced at the first observation point, 1 hour after rectal dosing, but continued throughout the hour observation period.