Antichlamydial activity of vaginal secretion

doi:10.1016/0002-9378(95)91491-9

American Journal of Obstetrics and Gynecology

Volume 172, Issue 4, Part 1, April 1995, Pages 1268-1272

https://doi.org/10.1016/0002-9378(95)91491-9 Get rights and content

Abstract

OBJECTIVE: The purpose of this study was to investigate the possible antichlamydial activity of vaginal secretion and to partially characterize the inhibitory principle.

STUDY DESIGN: Vaginal secretions obtained from 156 women attending a family planning or gynecologic outpatient clinic for contraceptive advice were studied for the influence on the inclusion formation of Chlamydia trachomatis in cycloheximide-treated McCoy cell cultures.

RESULTS: Vaginal secretions from 156 women inhibited the inclusion formation of Chlamydia trachomatis. The inhibitions was concentration dependent and the inhibitory principle had a molecular weight of <10,000 d. It was heat labile. It was not related to antichlamydial antibodies in vaginal secretions. Only three (2%) of the women had a positive culture for Chlamydia trachomatis. Three had immunoglobulin A and three had immunoglobulin G antichlamydial antibodies in vaginal secretions. Secretions of those with a vaginal pH of 3.5 to 4.5 decreased the chlamydial inclusion count by 75% compared with controls. The corresponding percentage for those with a pH of 5.0 to 6.0 was 48% and for those with pH >6 was 33%. Vaginal secretions of oral contraceptive users and nonusers did not differ in the capacity to decrease the chlamydial inclusion count, p > 0.01.

CONCLUSIONS: When vaginal secretions were added to McCoy cell cultures infected by Chlamydia trachomatis, the chlamydia inclusion number decreased. There was a correlation between pH of the vaginal secretion and the inhibitory principle. Oral contraceptive use had no influence on the inhibition.

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EVO100 prevents chlamydia and gonorrhea in women at high risk of infection
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Citation Excerpt :
An acidic vaginal pH and colonization of lactobacilli species in the vaginal mucosa are components of the multifaceted antimicrobial defense mechanisms in the vaginal fluid, which include the production of protective bacteriostatic and bactericidal compounds by lactobacillus species.2–6 It is thought that the naturally acidic vaginal environment may inhibit the acquisition of common STIs, including CT and GC.7–11 A prospective case-controlled study found that independent of other factors, women with CT infections were 6 times more likely to have pH>4.5 than controls.7
According to the Centers for Disease Control and Prevention, rates of infection for Chlamydia trachomatis and Neisseria gonorrhoeae are increasing in the United States. EVO100 is an investigational antimicrobial, pH-modulating, vaginal gel with active ingredients L-lactic acid, citric acid, and potassium bitartrate that is being evaluated for the prevention of sexually transmitted infections.
The objective of this phase 2B/3 study was to assess the efficacy and safety of EVO100 for the prevention of chlamydia and gonorrhea.
AMPREVENCE was a double-blinded, placebo-controlled, multicenter study based in the United States conducted over approximately 16 weeks in women at the age of 18 to 45 years who were at risk of urogenital chlamydia and gonorrhea infection. Enrolled women had been diagnosed as having and treated for chlamydia or gonorrhea ≤16 weeks before enrollment. Women received either EVO100 or placebo vaginal gel and were instructed to apply the study drug immediately before or up to 1 hour before each act of vaginal sexual intercourse. The primary and secondary endpoints were the prevention of urogenital chlamydia and gonorrhea, respectively. Exploratory outcomes include women’s overall satisfaction with EVO100.
In total, 860 women were randomized 1:1 to receive EVO100 (n=426) or placebo (n=434), and 764 women (EVO100, n=376; placebo, n=388) were documented as using the study drug at least once. Baseline characteristics were similar between treatment arms. Overall, women had a mean age of 27.7 years (standard deviation, 6.9) and body mass index of 28.9 kg/m² (standard deviation, 8.0). Most women were of White (54.3% [467 of 860]) or African American (41.6% [358 of 860]) race and of non-Hispanic/Latina ethnicity (67.1% [577 of 860]). The chlamydia infection rate in EVO100 users was 4.8% (14 of 289) compared with 9.7% (28 of 290) among placebo users (P=.0256), representing a relative risk reduction of 50%. For gonorrhea, the infection rate was 0.7% (2 of 280) in the EVO100 arm compared with 3.2% (9 of 277) in the placebo arm (P=.0316), representing a relative risk reduction of 78%. Increased efficacy was observed with increased adherence, and chlamydia infection rates were significantly reduced with increased adherence in the EVO100 group compared with placebo. Across both arms, there were similar rates of all-cause adverse events (EVO100, 21.3% [80 of 376]; placebo, 20.4% [79 of 388]) and treatment-related adverse events (EVO100, 7.2% [27 of 376]; placebo, 7.5% [29 of 388]). The most common adverse events in the EVO100 arm were vulvovaginal candidiasis (5.1% [19 of 376]), vaginal discharge (3.2% [12 of 376]), and urinary tract infection (3.2% [12 of 376]) and, in the placebo arm, bacterial vaginosis (4.6% [18 of 388]), urinary tract infection (2.6% [10 of 388]), and vaginal discharge (2.6% [10 of 388]). Few women discontinued owing to adverse events in either arm (EVO100, 1.1% [4 of 376]; placebo, 1.5% [6 of 388]). No treatment-related serious adverse events were reported. Most EVO100 users (88%) were satisfied or very satisfied with EVO100 after 16 weeks of use.
EVO100 significantly reduced the risk of chlamydia and gonorrhea infections in women at high risk of Chlamydia trachomatis and Neisseria gonorrhoeae infection and was well tolerated, with observed adverse events consistent with its known safety profile.
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This acidic environment is an important component of the natural vaginal defense against infections. In vitro studies have shown that an acidic pH prevents infection due to a variety of disease-causing organisms including HIV, herpes simplex, chlamydia, gonococci, Gardnerella and BV-associated organisms, Treponema pallidum and Haemophilus ducreyi [7–16]. This acidic pH is also inhospitable to sperm [17,18].
ACIDFORM is a candidate microbicide with spermicidal properties. A large Phase 3 trial is underway, and it is anticipated that this product will be approved for contraceptive use and marketed soon in the United States. The goal of this article is to critically review the evidence supporting the properties, safety profile and different uses of ACIDFORM gel.
We searched PubMed and Medline for any published literature on ACIDFORM.
ACIDFORM is an acidifying agent that works by lowering the vaginal pH to enhance the normal vaginal defenses. In addition to strong acid-buffering properties, ACIDFORM has high bioadhesive and viscosity-retaining properties. Several Phase 1 clinical trials have demonstrated the vaginal safety of ACIDFORM used alone or in combination with a diaphragm, although dose-dependent side effects appear to be present. Studies investigating the efficacy of ACIDFORM against sexually transmitted infections (STIs) are promising, but further trials are needed.
The properties of ACIDFORM offer many advantages for use, either alone or in combination with another active ingredient, such as Tenofovir. Potential applications for ACIDFORM include use as a personal lubricant, a vaginal contraceptive (alone or with a barrier method) and a microbicidal product or as a formulation vehicle for an active ingredient.
ACIDFORM is a candidate female-controlled vaginal preparation with microbicidal and spermicidal properties. A dual protection method could prevent unwanted pregnancies and reduce the risk of STI acquisition.
UniPron is A Fully Effective Non-hormonal Reversible Contraceptive in Baboon Model (Papio Anubis)
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To determine the safety and efficacy of UniPron as a reversible contraceptive.
Vaginal swabs were obtained before and after UniPron administration, cultured onto appropriate culture media and bacteria identification was done based on type of media used, Gram stain reactions, colony morphology and biochemical tests. Vaginal biopsy tissues were processed using paraffin wax method, stained with hematoxylin and eosin and examined under light microscopy to determine the effect of the product on vaginal tissues. The effect of UniPron on sperm was examined by mixing the product with electroejaculated spermatozoa in vitro at different concentrations. For efficacy studies, male baboons of proven fertility were mated with UniPron treated or untreated females of proven fertility during the fertile stages.
All the five females (100%) that were treated with UniPron did not conceive and they regained total fertility when the treatment was stopped while all the controls conceived. At a concentration of 40%, UniPron completely immobilized spermatozoa in an in-vitro system. UniPron mechanism of action was by lowering the vaginal pH and on application in baboon, the pH was lowered for at least 3 h after which it went back to normal.
As we plan for a study to test UniPron as a microbicide to prevent STIs including HIV, our current study has established that this novel product is effective in contraception and harmless to vaginal tissues and vaginal microbial flora in a baboon model (Papio anubis).
Vaginal safety after use of a bioadhesive, acid-buffering, microbicidal contraceptive gel (ACIDFORM) and a 2% nonoxynol-9 product
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ACIDFORM is a microbicidal and contraceptive candidate with strong buffering capacity.
This was a Phase I blinded, randomized and crossover clinical study on two products, ACIDFORM and a commercial nonoxynol-9 (N-9) product (2%), evaluating their vaginal safety in 20 couples aged between 19 and 45 years. The women had regular menses, underwent previous tubal ligation, were not breast-feeding, had no vaginal sign and symptom and were in a stable partnership; both partners had no previous STI. Colposcopy, vaginal microbiology, inflammation markers and subject complaints were studied after coitus. Women were randomly assigned sequentially to receive ACIDFORM 0–30 min (0–30 min before intercourse), ACIDFORM 8–10 h (8–10 h before intercourse) or N-9 0–30 min after a control cycle.
Mild/moderate vulvar irritation was observed in five postcoital test colposcopies, burning and pruritus were reported in six treated cycles and non-irritation-related symptoms were found in five cycles with different treatments. No difference in vaginal pH, Nugent scores, H₂O₂-producing lactobacillus or leukocytes and interleukin 6 in the cervicovaginal lavage was found between the treatment and control cycles.
ACIDFORM appears to be safe for clinical use once a day. There is a potential spermicidal–microbicidal role for ACIDFORM as a vaginal flora helper or as a vehicle for products, except N-9.
pH-sensitive hydrogel based on a polyaspartamide derivative
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A pH-sensitive hydrogel was prepared by UV irradiation technique. Starting polymer was obtained from α,β-poly (N-2-hydroxyethyl)-DL-aspartamide (PHEA) partially derivatized with glycidyl methacrylate (PHG). The PHG copolymer was cross-linked by UV irradiation in the presence of methacrylic acid (MA) to form a pH sensitive hydrogel. The cross-linked matrix shaped as microparticles was characterized by FT-IR spectrophotometry, XPS, X-ray diffraction, SEM and particle size distribution analyses. Moreover, to have information about water affinity of the prepared sample, swelling measurements were carried out in aqueous media mimicking some biological fluids. In order to employ the prepared network as a pH-sensitive drug delivery system, propionyl-L-carnitine, chosen as a model drug, was entrapped into this hydrogel both during the irradiation process and after cross-linking reaction by a soaking technique. In vitro release studies showed that the drug release rate depends on the different swelling of the network as a function of the environmental pH as well as on the different drug loading method.
Postcoital testing after the use of a bio-adhesive acid buffering gel (ACIDFORM) and a 2% nonoxynol-9 product
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ACIDFORM is a gel already shown to be safe in vaginal use during six consecutive days through colposcopic observation. A randomized, blinded, crossover study was carried out to compare the spermicidal effect of ACIDFORM to that of a commercial 2% nonoxynol-9 (N-9) product. Twenty sexually active, sterilized women, aged 19–45 years, with regular cycles, normal gynecological exam, no previous sexually transmitted infection (STI) and stable partner willing to undergo four postcoital tests (PCTs) at midcycle during four different menstrual cycles, were enrolled in the study. Known allergy to N-9 or ACIDFORM, oligospermic partner, chronic diseases, use of hormones, previous treatment for STI or presence of STI at screening tests were criteria for exclusion. ACIDFORM or N-9 product administered 0–30 min precoitus or ACIDFORM given 8–10 h precoitus significantly reduced the mean number of progressively motile sperm compared to control cycles (0.19, 0.07, 0.75 vs. 17.94, respectively, p<.05, Wilcoxon test). All treated cycles had five or fewer progressively motile sperm in midcycle cervical mucus, confirming in vivo the spermicidal effect of ACIDFORM previously observed in vitro and in animal models.

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American Journal of Obstetrics and Gynecology

Abstract

References (25)

Diagnostic procedures in vaginitis

Eur J Obstet Gynecol Reprod Biol

Observations on candidal vaginitis

Human cervical mucus contains large amounts of prostaglandins

Fertil Steril

Preliminary observations on lactoferrin secretion in human vaginal mucus: variation during the menstrual cycle, evidence of hormonal regulation, and implications for infection with Neisseria gonorrhoeae

Am J Obstet Gynecol

Antichlamydial activity of cervical secretion of different phases of the menstrual cycle and influence of hormonal contraceptives

Contraception

Characteristics of three vaginal flora patterns assessed by Gram stain among pregnant women

Oral contraceptive use and the risk of chlamydial and gonococcal infections

Am J Obstet Gynecol

Genitourinary mucosal defences

Assay of fibronectin in vaginal fluid and role of fibronectin in bacterial colonization

Inhibitory effect on the formation of chlamydia inclusion in McCoy cells by seminal fluid and some of its components

Invest Urol

Antibacterial activity of human cervical mucus

Jpn J Antibiot

Antibacterial activity of cervical mucus in pregnant and non-pregnant women

Jpn J Antibiot

Cited by (33)

EVO100 prevents chlamydia and gonorrhea in women at high risk of infection

ACIDFORM: A review of the evidence

UniPron is A Fully Effective Non-hormonal Reversible Contraceptive in Baboon Model (Papio Anubis)

Vaginal safety after use of a bioadhesive, acid-buffering, microbicidal contraceptive gel (ACIDFORM) and a 2% nonoxynol-9 product

pH-sensitive hydrogel based on a polyaspartamide derivative

Postcoital testing after the use of a bio-adhesive acid buffering gel (ACIDFORM) and a 2% nonoxynol-9 product

General obstetrics and gynecologyAntichlamydial activity of vaginal secretion

Abstract

Eur J Obstet Gynecol Reprod Biol

Fertil Steril

Am J Obstet Gynecol

Contraception

Am J Obstet Gynecol

Genitourinary mucosal defences

Assay of fibronectin in vaginal fluid and role of fibronectin in bacterial colonization

Inhibitory effect on the formation of chlamydia inclusion in McCoy cells by seminal fluid and some of its components

Invest Urol

Antibacterial activity of human cervical mucus

Jpn J Antibiot

Antibacterial activity of cervical mucus in pregnant and non-pregnant women

Jpn J Antibiot

General obstetrics and gynecology
Antichlamydial activity of vaginal secretion