Safety and efficacy evaluations for vaginal and rectal use of BufferGel in the macaque model.

BACKGROUND: The nonhuman primate model allows for safety and efficacy testing of topical microbicide products. GOAL: The goal of this study was to evaluate the safety and efficacy of vaginal and rectal applications of BufferGel (ReProtect, Inc.). STUDY DESIGN: The safety of repeated product applications was evaluated by microflora, pH, vaginal colposcopy, and rectal lavage. To test efficacy in preventing chlamydia, infection was documented by culture and nucleic acid amplification tests. RESULTS: Repeated vaginal or rectal applications of BufferGel were not associated with significant changes in microflora. BufferGel use had a transient acidifying effect on vaginal and rectal pH. Colposcopic observations remained relatively normal in all test animals. A slightly increased incidence of epithelial desquamation was noted after rectal product use compared with the control group. BufferGel did not prevent cervical or rectal chlamydial infection. CONCLUSION: BufferGel has an acceptable safety profile after repeated vaginal and rectal use, but does not prevent chlamydial infection in the macaque models.

Effects of multiple applications of benzalkonium chloride and nonoxynol 9 on the vaginal epithelium in the pigtailed macaque (Macaca nemestrina).

OBJECTIVE: Safe and effective vaginally applied microbicides could help to control the continuing spread of sexually transmitted diseases. STUDY DESIGN: This study used nonhuman primates to test the effects of multiple applications of nonoxynol 9, benzalkonium chloride, or a combination on vaginal flora and lower reproductive tract tissues. Fourteen monkeys (Macaca nemestrina) received daily vaginal applications of nonoxynol 9, benzalkonium chloride, or both for 3 to 4 days. Vaginal microflora and colposcopic observations were made at baseline and during and after completion of treatments. Cervical biopsy specimens were collected from a subset of animals. RESULTS: Cervical erythema and vaginal erythema were observed in all 3 treatment groups. Cervical papillae and epithelial disruption were present in both the nonoxynol 9 and the nonoxynol 9 plus benzalkonium chloride groups. Vaginal epithelial disruption was noted in both the benzalkonium chloride and the nonoxynol 9 plus benzalkonium chloride groups. Cervical biopsy specimens from each group revealed acute inflammatory infiltrates with occasional plasma cells and lymphoid follicles. Detection of most microorganisms, including viridans streptococci, decreased in the benzalkonium chloride and the nonoxynol 9 plus benzalkonium chloride groups. Detection of Lactobacillus species decreased in the benzalkonium chloride group. All microflora levels recovered after several days without microbicide use. CONCLUSIONS: Although nonoxynol 9 is currently the only microbicide approved for use as a spermicide in the United States, its repeated use may be detrimental to the epithelial tissues of the female reproductive tract. Benzalkonium chloride, currently approved for use in other countries, not only may damage epithelial tissues but also appears to reduce the population of potentially protective Lactobacillus species in the vagina.

Effects of doxycycline and antiinflammatory agents on experimentally induced chlamydial upper genital tract infection in female macaques.

To evaluate the effects of antimicrobial and antiinflammatory drugs on oviductal pathology in chronic chlamydial upper genital tract infection, the fallopian tubes of 40 female Macaca nemestrina were inoculated with Chlamydia trachomatis and randomly assigned to treatment with doxycycline (n = 10), doxycycline plus ibuprofen (n = 10), doxycycline plus triamcinolone (n = 10), or placebo (n = 10). Before therapy, all animals were positive for culture or ligase chain reaction (or both), and laparoscopy demonstrated the presence of upper genital tract pathology. After therapy, cervical cultures remained positive in 5 animals given placebo versus 0 given doxycycline alone (P = .03), 0 given doxycycline plus ibuprofen (P = .03), and 1 given doxycycline plus triamcinolone (P = .14). At hysterectomy, neither gross nor histologic pathology was affected by any of the treatment regimens, but immunocytochemistry and in situ hybridization evidence of persistent tubal infection was significantly more frequent among animals given placebo or doxycycline plus antiinflammatory agents than among those given doxycycline alone.

Effects of nonoxynol-9 on vaginal microflora and chlamydial infection in a monkey model.

BACKGROUND AND OBJECTIVES: Nonoxynol-9, an intravaginal microbicide, is chlamydiacidal in vitro but also cytotoxic. This study examines the effects of nonoxynol-9 in vivo, using a pigtail macaque model of chlamydial cervicitis. GOALS: To establish a minimum infectious dose of Chlamydia trachomatis in the macaque, and to observe the effects of a single dose of nonoxynol-9 on efficiency of chlamydial infection, vaginal microflora, and cervicovaginal irritation. STUDY DESIGN: The effects of 4% nonoxynol-9, C. trachomatis (5,000 or 10,000 IFU) or both nonoxynol-9 application and chlamydial infection were studied in 17 macaques. RESULTS: Following a single application of nonoxynol-9, chlamydial infection was prevented in 4 of 6 monkeys infected with 10,000 IFU; there was a transient decrease in anaerobic gram-negative rods (P < 0.05) and Peptostreptococci (P > 0.05), but no change in Lactobacillus. Mild cervicovaginal irritation was observed in the monkeys. CONCLUSIONS: A single dose of nonoxynol-9 causes minimal vaginal flora and epithelial irritation, and may be useful for prevention of chlamydial infection.

The vaginal microflora of pig-tailed macaques and the effects of chlorhexidine and benzalkonium on this ecosystem.

BACKGROUND AND OBJECTIVES: To characterize normal vaginal microflora of pig-tailed macaques and to evaluate two commonly used intravaginal compounds, chlorhexidine (CHG), a vaginal antiseptic (Surgilube, E. Fougera, Melville, NY), and benzalkonium chloride (BZK) (spermicidal contraceptive) in this monkey model to assess effects on the vaginal microflora. STUDY DESIGN: Vaginal swabs were collected for microbiologic analysis to characterize normal flora. Subsequently, the vagina was exposed to either CHG or BZK twice at 24-hour intervals. RESULTS: The vaginal microflora of 26 pig-tailed macaques was found to be remarkably similar to the vaginal flora of the human with respect to frequency of vaginal colonization by H2O2-producing lactobacilli, Prevotella species, and several other microorganisms. After two vaginal applications at 24-hour intervals, CHG had only small effects on the vaginal microflora of five animals. By contrast, BZK applied by the same protocol had profound adverse effects on the lactobacilli and Peptostreptococcus and more transient effects on vaginal Prevotella and viridans streptococci of six animals. CONCLUSIONS: These observations demonstrate that the vaginal microflora of the pig-tailed macaque is a useful model in which to further evaluate newly developed intravaginal contraceptives that may be microbicidal and/or virucidal before widespread intravaginal use in women.