Safety evaluation of 1% tenofovir gel in healthy men.

This study was conducted to determine the safety of tenofovir (TFV) gel, a potential microbicide, following seven consecutive daily penile applications. Eighteen circumcised and 18 uncircumcised healthy men were randomly assigned to TFV gel versus K-Y Jelly in a 2:1 ratio within circumcision group. TFV gel or K-Y Jelly was applied onto the penis at bedtime and washed off 6-10 hours later. Safety was assessed by reported symptoms, findings and laboratory tests. Three of 24 (13%) men in the TFV group reported mild genital symptoms compared with two of 11 (18%) men in the K-Y group. Few mild genital findings were observed and no significant systemic toxicities were reported or observed. TFV gel applied to the penis for seven days was well tolerated locally and systemically and it is unlikely that male partners exposed to small amounts of TFV gel will experience significant genital or systemic toxicity.

The use of colposcopy in assessing vaginal irritation in research.

Since the early 1990s, colposcopy of the vagina and cervix has been used in the development of vaginal products in order to detect epithelial changes that may increase the likelihood of HIV or acquisition of other sexually transmitted diseases. As part of a continued effort to examine and define the role of colposcopy in a research setting, the Contraceptive Research and Development Program (CONRAD) and the International Working Group on Microbicides (IWGM), in association with the United Nations Program for AIDS (UNAIDS) sponsored a conference entitled, 'The Use of Colposcopy in Assessing Vaginal Irritation in Research', held in Washington, DC in January 1999. This is a report of that conference. The World Health Organization's colposcopy procedure and nomenclature, published in 1995, were reviewed and changes were recommended. The revised procedure involves colposcopic examination of the external genitalia, naked eye examination of the cervix, fornices, and vaginal walls, followed by lavage and colposcopic examination of those areas, and sampling as appropriate for microscopic examination. Revised nomenclature replaces the terms used for findings with descriptions of what is actually seen. Digital video imaging and testing for inflammatory markers may be adjuncts to colposcopy and should be further studied. Other areas requiring additional research include the natural history of colposcopic changes, factors other than product use that may affect colposcopic findings, the clinical significance of findings, and the procedure which best assesses these findings.

The effect of one injection of Depo-Provera on the human vaginal epithelium and cervical ectopy.

Two studies in rhesus monkeys have shown that progesterone implants, Depo-Provera and Norplant, were associated with vaginal thinning. Progesterone implants have also been associated with an increased risk of simian immunodeficiency virus (SIV) acquisition. This study in 16 women was done to assess vaginal epithelial thickness and number of cell layers from biopsies taken in the untreated follicular and luteal phases, and at 1 month and 3 months after administration of Depo-Provera. There was no significant change over time in either parameter from biopsies obtained in the luteal phase compared with those at either time after Depo-Provera administration. There was also no change in the mean number of Langerhans cells in vaginal wall specimens and no change in cervical ectopy. It appears that women do not respond to exogenous progestins with the dramatic vaginal thinning seen in rhesus monkeys.

PIP: This study assesses vaginal epithelial thickness and number of cell layers from biopsies taken in the untreated follicular and luteal phases and at 1 month and 3 months after administration of Depo-Provera. Subjects were seen at the CONRAD Clinical Research Center at the Eastern Virginia Medical School, Norfolk, Virginia. Findings showed that there was no significant change over time in either parameter from biopsies obtained in the luteal phase compared with those at either time after Depo-Provera administration. There was also no change in the mean number of Langerhans cells in vaginal wall specimens and no change in cervical ectopy. The dramatic vaginal thinning seen in rhesus monkeys was not observed among these subjects.

A phase I comparative study of contraceptive vaginal films containing benzalkonium chloride and nonoxynol-9. Postcoital testing and colposcopy.

Benzalkonium chloride (BZK) has been shown in in vitro and in vivo studies to immobilize sperm, to be active against STD-causing organisms, and to penetrate and thicken cervical mucus. A US clinical study of a sponge containing 60 mg BZK showed life table pregnancy rates at 6 and 12 months of 11.7 and 18.9 per 100 women, respectively. BZK is not currently marketed in the US as a contraceptive. The present study aimed to assess 1) the ability of a new contraceptive vaginal film containing either of two doses of BZK to prevent the penetration of sperm into midcycle cervical mucus; 2) the effect of the film on the vaginal epithelium; and 3) the acceptability of the film. All results were compared with VCF, a currently marketed film containing nonoxynol-9 (N-9). Ten women underwent two baseline cycles of postcoital testing in which no film was used, followed by three test cycles in which Allendale-BZK film, a new film containing either 19 or 25 mg BZK, or VCF, containing 70 mg N-9, was used. The sequence of testing cycles was randomized. In each cycle, condoms were used prior to midcycle, then a midcycle cervical mucus specimen was examined to ensure midcycle characteristics and the absence of sperm. Each woman then had intercourse using either no film (baseline cycles) or a test film (test cycles) and returned 2-3 h afterwards. Cervical mucus was again assessed for adequacy and the presence of sperm. Each woman also underwent colposcopy, using a protocol developed by the World Health Organization. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 22.2; second baseline cycle, 22.1; test cycle with film containing 19 mg BZK, 0.2; test cycle with film containing 25 mg BZK, 0.0; and test cycle with VCF containing 70 mg N-9, 0.0. There was no significant difference between baseline cycles or among test cycles in the average number of progressively motile sperm seen (p = 0.78 and p > or = 0.75, respectively). The average number of progressively motile sperm seen in each test cycle did, however, differ significantly from the average number seen in either baseline cycle (p < 0.01). Colposcopy showed superficial de-epithelialization without underlying inflammation in 15-20% of baseline cycles, regardless of whether colposcopy was done before or after coitus; in 50% of cycles in which either dose of BZK was used; and in 69% of cycles in which VCF was used. In all cases women were asymptomatic. Erythema and petechiae were also seen on colposcopy although at a lower frequency than de-epithelialization. There was no difference in the acceptability of the films. A vaginal contraceptive containing either 19 or 25 mg BZK in a new film base appears to be comparable with VCF in preventing sperm from entering midcycle cervical mucus and may be somewhat less disruptive to the vaginal epithelium.

PIP: Both in vitro and in vivo studies have confirmed the capability of benzalkonium chloride (BZK) to immobilize sperm, protect against sexually transmitted pathogens, and penetrate and thicken cervical mucus. In this Phase I study, 10 US women underwent 2 baseline cycles followed by 3 experimental cycles in which either a new contraceptive vaginal film containing 19 or 25 mg of BZK or a currently marketed film containing 70 mg of nonoxynol-9 (N-9) was used. After a midcycle cervical mucus specimen was analyzed, each woman had intercourse using either no film or a test film and was evaluated 2-3 hours later. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 22.2; second baseline cycle, 22.1; test cycle with film containing 19 mg BZK, 0.2; test cycle with film containing 25 mg BZK, 0.0; and test cycle with film containing 70 mg N-9, 0.0. Colposcopy revealed superficial de-epithelialization without underlying inflammation in 15-20% of baseline cycles, 50% of BZK test cycles, and 69% of cycles in which the N-9 film was used. Women rated both films as neutral or pleasant in terms of appearance, smell, and feel. These findings suggest that contraceptive vaginal films containing either 19 or 25 mg of BZK are as effective as N-9 containing films and may be somewhat less disruptive to the vaginal epithelium. However, since each woman used each BZK film only once, the effects of multiple use on the vaginal epithelium and microflora require further study.

An evaluation of the amount of nonoxynol-9 remaining in the vagina up to 4 h after insertion of a vaginal contraceptive film (VCF) containing 70 mg nonoxynol-9.

The objectives of this study were to determine the amount of nonoxynol-9 (N-9) remaining in the vagina 30 min and 1, 1.5, 2, and 4 h after vaginal insertion of a single sheet of VCF containing 70 mg N-9 and to compare these results to the manufacturer's instructions for use of this product. A new method of vaginal lavage was used to obtain samples for N-9 determination. This was an open-label, noncomparative, pharmacokinetic study in 12 healthy women volunteers not at risk for pregnancy. The study consisted of a screening visit followed by five test visits approximately 1 month apart and a final visit 1 week after all test visits were completed. At each test visit, the investigator inserted a single sheet of VCF in the vagina of the volunteer at midcycle. The volunteer remained in the clinic and underwent vaginal lavage with normal saline after one of five specified time intervals had elapsed. The sequence of the intervals completed by each volunteer was determined by randomization. When undissolved film was found in the vagina, it was removed prior to lavage and assayed for N-9 content separately from that recovered in lavage fluid. It was assumed that the N-9 in undissolved film would not contribute significantly to sperm immobilization. Between 18.5 and 28.5 mg of N-9 were recovered in lavage fluid after intervals of 0.5, 1, 1.5, and 2 h. These levels did not differ statistically (p > 0.05). The amount of N-9 recovered dropped significantly at 4 h to 11.0 mg. If it is assumed that an N-9 concentration of 0.100 mg/mL is required to immobilize sperm in vitro, this study suggests that the amount of N-9 remaining in the vagina in the form of dissolved film up to 4 h after insertion of VCF is sufficient to immobilize sperm. The lavage procedure may not have recovered all N-9 remaining in the vagina. However, intercourse did not take place between insertion and lavage; if it had, the proportion of the film remaining undissolved and the total amount N-9 remaining in the vagina at the time of examination might have been affected.

PIP: The amount of nonoxynol-9 (N-9) remaining in the vagina 0.5, 1.0, 1.5, 2.0, and 4.0 hours after vaginal insertion of a single sheet of a contraceptive film (VCP) containing 70 mg of N-9 was investigated in a pharmacokinetic study involving 12 US women. At each of 5 test visits, approximately 1 month apart, a single sheet of VCF was inserted at midcycle. Vaginal lavage with normal saline was then performed after 1 of the 5 specified time intervals had elapsed. At 30 minutes, an average of 34.4 mg (49% of the total N-9) could be recovered. After intervals of 1.0, 1.5, and 2.0 hours, 18.5-28.5 mg of N-9 was recovered in lavage fluid. The amount of recovered N-9 dropped significantly to 11.0 mg after 4.0 hours. It is assumed that an N-9 concentration of 0.100 mg/mL is required to immobilize sperm. Thus, the amount of N-9 remaining in the vagina up to 4.0 hours after insertion of VCF is sufficient for contraception. The VCF label states that intercourse may take place 15 minutes after film insertion. Although lavage was not performed at this time point, it can be assumed that at least 49% of the original N-9 would be present. Since this study is limited by the fact that intercourse did not take place, future studies should include postcoital measures of the amount of N-9 persisting at various intervals.

A phase I comparative study of three contraceptive vaginal films containing nonoxynol-9. Postcoital testing and colposcopy.

The objectives of this study were 1) to assess the ability of a new contraceptive vaginal film containing two doses of nonoxynol-9 (N-9) to prevent the penetration of sperm into midcycle cervical mucus, and 2) to determine the effect of the film on the vaginal epithelium. The novel formulation was compared with VCF (a currently marketed film also containing N-9). Ten women underwent two baseline cycles of postcoital testing in which no film was used, followed by three test cycles in which Allendale-N9 film, a new film containing either 100 or 130 mg N-9, or VCF containing 70mg N-9 was used. The sequence of testing cycles was randomized. In each cycle, condoms were used prior to midcycle, then a midcycle cervical mucus specimen was examined to ensure midcycle characteristics and the absence of sperm. Each woman then had intercourse using either no film (baseline cycles) or a test film (test cycles) and returned 2-3 h afterwards. Cervical mucus was again assessed for adequacy and the presence of sperm. Each woman also underwent colposcopy using a protocol developed by the World Health Organization. The average number of progressively motile sperm seen per high power field were as follows: average of the two baseline cycles, 19.3; test cycle with Allendale-N9 film containing 100 mg N-9, 0.6; test cycle with Allendale-N9 film containing 130 mg N-9, 0.9; and test cycle with VCF, 0.5. There was no significant difference between baseline cycles or between test cycles in the number of progressively motile sperm per high power field (HPF) seen (p = 0.31 and p > or = 0.50, respectively). The average number of motile sperm seen in each test cycle did, however, differ significantly from the number in either baseline cycle (p < 0.02). The majority of colposcopic examinations were normal. In one baseline cycle and eight test cycles, colposcopy showed superficial de-epithelialization without underlying inflammation. There was no apparent dose response and in all cases the volunteers were asymptomatic. A vaginal contraceptive containing either 100 or 130 mg N-9 in a new film base appears to be safe and comparable to VCF in preventing sperm from entering midcycle cervical mucus.

PIP: In this Phase I study, 10 US women underwent sequential testing of 3 contraceptive vaginal films containing nonoxynol-9 (N-9): a new Allendale-N-9 film containing either 100 or 130 mg of the spermicide or the commercially available VCF product containing 70 mg of N-9. After a midcycle cervical mucus specimen was collected, women had intercourse using either no film (2 baseline cycles) or a test film and returned 2-3 hours later for further testing. The average number of progressively motile sperm seen per high power field were as follows: average of the 2 baseline cycles, 19.3; test cycle with Allendale-N-9 film containing 100 mg N-9, 0.6; test cycle with Allendale-N-9 film containing 130 mg N-9, 0.9; and test cycle with VCF, 0.5. In 1 baseline and 8 test cycles, colposcopy revealed superficial de-epithelialization. De-epithelialization occurred least often when the 100 mg Allendale film was used. None of the women who experienced de-epithelialization reported symptomatic irritation. These findings indicate that the new contraceptive product containing either 100 or 130 mg of N-9 is safe and comparable to the VCF product in terms of preventing sperm from entering midcycle cervical mucus.

A phase I study of Femcap used with and without spermicide. Postcoital testing.

The objectives of the study were to assess the ability of the Femcap, a new vaginal contraceptive device made of silicone and designed to fit snugly around the cervix to prevent the penetration of sperm into midcycle cervical mucus when used with and without spermicide; and to compare it with the standard contraceptive diaphragm used with spermicide. Eight women underwent two baseline cycles of postcoital testing in which no device was used, followed by three test cycles in which Femcap with spermicide, Femcap with nonspermicidal lubricant (K'Y gel) or the Ortho All-Flex diaphragm with spermicide was used. The sequence of testing cycles was randomized. In each cycle, condoms were used prior to midcycle, then a midcycle cervical mucus specimen was examined to ensure midcycle characteristics and the absence of sperm. Each woman then had intercourse using either no device (baseline cycles) or the prescribed device (test cycles) and returned 2-3 h afterwards. Cervical mucus was again assessed for adequacy and the presence of spermatozoa. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 18.0; second baseline cycle, 17.8; test cycle with Femcap used with nonspermicidal lubricant, 0.1; test cycle with Femcap used with spermicide, 0.2; and test cycle with the diaphragm used with spermicide, 0.0. There was no significant difference between baseline cycles or among test cycles in the average number of progressively motile sperm seen (p > 0.05). The average number of progressively motile sperm seen in each test cycle did, however, differ significantly from the average number seen in either baseline cycle (p < 0.05). Femcap, used with either a spermicidal lubricant or a nonspermicidal lubricant, appears to be comparable with the diaphragm used with spermicide in preventing sperm from entering midcycle cervical mucus.

PIP: A Phase I postcoital study assessed the capability of Femcap, a new vaginal contraceptive device made of silicone, to prevent sperm from entering midcycle cervical mucus. After 2 baseline cycles of postcoital testing in which no device was used, 8 US women underwent 3 test cycles in which Femcap with spermicide, Femcap with a nonspermicidal lubricant (KY gel), or the Ortho All-Flex diaphragm with spermicide was used. The sequence of testing cycles was randomized. The average number of progressively motile sperm seen per high power field was as follows: first baseline cycle, 18.0; second baseline cycle, 17.8; test cycle with Femcap used with nonspermicidal lubricant, 0.1; test cycle with Femcap used with spermicide, 0.2; and test cycle with the diaphragm used with spermicide, 0.0. These findings indicate that Femcap, used with either a spermicide or a nonspermicidal lubricant, is comparable to the diaphragm in terms of its ability to prevent the penetration of sperm into midcycle cervical mucus.

Lea's Shield: a phase I postcoital study of a new contraceptive barrier device.

Lea's Shield is a new vaginal barrier contraceptive that may offer advantages over existing methods. It is made of silicone which is resistant to petroleum-based lubricants, does not absorb odors, and does not cause allergic reactions in users with latex sensitivity. It has an anterior loop for ease of insertion and removal and a one-way flutter valve. Its novel design has sufficient volume to fill the posterior fornix, which helps keep it in place and prevent sperm from entering the cervical os. This study evaluated with a standard postcoital test (PCT) the ability of the Lea's Shield used with spermicide or non-spermicidal lubricant to prevent sperm from entering midcycle cervical mucus. Ten sterilized women underwent four PCT cycles: one cycle in which no contraceptive barrier was used (a baseline cycle) and 3 cycles in which one of the following was used: Lea's Shield with spermicide, or with non-spermicidal lubricant, or the contraceptive diaphragm used with spermicide. All volunteers demonstrated more than 5 progressively motile sperm per high power field in the cervical mucus after intercourse in the baseline cycle. No motile sperm were found in the cervical mucus in any cycle in which Lea's Shield or the diaphragm was used with spermicide. No motile sperm were found in cervical mucus in 9 of 10 cycles in which Lea's Shield was used without spermicide. Only two progressively motile sperm were present in the cervical mucus of one volunteer who used the shield with non-spermicidal lubricant.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: The results of a Phase I postcoital study of Lea's Shield, a new vaginal barrier contraceptive, suggest that this device is as effective as the vaginal diaphragm, even when used without spermicide. Evaluated was the ability of the Lea's Shield to prevent sperm from entering midcycle cervical mucus. Ten sterilized women underwent a baseline cycle followed by three additional cycles under one of the following conditions: Lea's Shield with spermicide, Lea's Shield with a nonspermicidal lubricant, or standard vaginal diaphragm with spermicide. In the baseline cycle, all subjects demonstrated more than five progressively motile sperm per high power field in the cervical mucus after intercourse. No sperm were detected in the post-intercourse cervical mucus in either the women who used the standard diaphragm with spermicide or those using the Lea's Shield with spermicide. One volunteer who used the Lea's Shield without spermicide had two progressively motile sperm in the cervical mucus; however, this involved a small size device that is no longer manufactured and was considered unlikely to result in pregnancy. There were no side effects reported by Lea's Shield users. Advantages of this new device include its silicone composition (more resistant to heat and deterioration, less absorbent of odors, and less likely to cause allergic reactions than latex), anterior loop for ease of insertion and removal, one-way flutter valve, and lack of pressure on the urethra.