Biocompatible polyvinyl alcohol and RISUG® blend polymeric films with spermicidal potential.

Majority of the commercially available vaginal contraceptives encompasses cervicovaginal membrane disrupting detergent molecules as pharmacologically active ingredients. Development of a tissue-compatible vaginal contraceptive agent is necessary to circumvent the existing demand for female contraception in the reproductive healthcare sector. With this objective, the present study delineates the use of RISUG® based non-hormonal female contraceptive films. RISUG® was blended with polyvinyl alcohol (PVOH) to formulate biodegradable intra-vaginal contraceptive films. The formulated films were characterized for their thermal, physiochemical and biological features. The results showed that both RISUG® and PVOH were miscible and interacted at the intermolecular level. Variations in the concentration of RISUG® resulted in the changes in physicochemical, thermal and rheological characteristics of the formulated blends. In vitro toxicological assay of the polymeric formulations did not show any significant toxicity. However, the blend films retained spermicidal potential of RISUG®. Furthermore, in vivo toxicological evaluation of the polymeric blend in the rat model revealed about their biocompatibility with no significant organ toxicity, hematological and biochemical alterations. These results together confirm the potential applicability of the PVOH:RISUG® blend films as a vaginal contraceptive.

An overview of properties of Amphora (Acidform) contraceptive vaginal gel.

INTRODUCTION: Although only a minority of contracepting women rely solely on spermicides, they may soon be the only ongoing female method available without a prescription in the United States. Spermicides are also combined with other methods for additional pregnancy protection and/or lubrication. Nonoxynol-9 (N-9), the active ingredient in most spermicides, is cytotoxic and may increase risk of transmission of HIV and other sexually transmitted infections, especially in high-risk women. Amphora (previously called Acidform) is a noncytotoxic spermicide composed of a series of generally regarded as safe compounds, which maintains the acidity of the vagina following coitus to immobilize and kill sperm. Amphora is currently Food and Drug Administration-approved as a vaginal lubricant. Amphora is currently being tested in a multicenter Phase III contraceptive trial. AREAS COVERED: This paper describes key properties of Amphora, including its acid-buffering abilities, viscosity, stability, bioadhesiveness, and tolerability. EXPERT OPINION: Amphora is a nontoxic spermicide that maintains the pH within the vagina at levels less than 5.0 for hours, which immobilizes and kills sperm as well as many sexually transmitted pathogens. If the current clinical trial demonstrates safety, efficacy, and tolerability of Amphora as a contraceptive, it would represent a viable alternative to N-9. Its potential as a microbicide warrants further investigation.

A CCR5 antagonist-based HIV entry inhibitor exhibited potent spermicidal activity: Potential application for contraception and prevention of HIV sexual transmission.

B07 is a small-molecule CCR5 antagonist-based HIV-1 entry inhibitor that is being developed as an anti-HIV microbicide for preventing sexual transmission of HIV. Here we evaluated its spermicidal and contraceptive potential, including sperm motility, plasma membrane integrity, and contraceptive efficacy tested in rabbits. We found that B07 inhibited sperm motility and movement patterns in a concentration- and time-dependent manner. Within 30 min, B07 induced sperm immobilization with the minimum 100% effective concentration and median effective concentration of 640.0 and 64.4 µg/mL, respectively. The hypo-osmotic swelling test showed that plasma membranes of B07-treated sperms exhibited slight disruption, as verified by electron micrographs. In both B07 gel and N-9 gel groups, not a single implantation site or embryo was observed based on the contraceptive efficacy test in rabbits, indicating that B07 could effectively block the potential of sperm to reach and/or fertilize oocytes. The safety profile of B07 in vivo was evaluated by use of an optimized rabbit vaginal irritation test. While the pathological scores of the N-9 gel group was 14.67 ±â€¯1.21, those of the blank control and B07 gel groups were 2.17 ±â€¯0.76 and 4.00 ±â€¯0.89, respectively, which were within the clinically acceptable range (<8). The proportion of inflammatory cells and CD45+ cells in the cervicovaginal lavages of the B07 gel group showed no significant change compared to those of the control group. Therefore, our results confirmed that B07 exhibited significant spermicidal and contraceptive effects, suggesting its potential for development as a microbicidal spermicide for contraception and prevention of HIV sexual transmission.

Meaning-making matters in product design: users' sensory perceptions and experience evaluations of long-acting vaginal gels and intravaginal rings.

OBJECTIVE: Users' sensory perceptions and experiences of intravaginal products can inform acceptability and adherence. Focusing on the meanings women derive from formulation/device characteristics facilitates developers' design iterations toward optimizing user experience. We investigated how users of long-acting gels and intravaginal rings (IVRs) impute meaning to characteristics that may affect future product use. STUDY DESIGN: Focus groups were conducted with contraceptive IVR and vaginal lubricant users. Current perceptibility science and historical theory on the cultural acceptability of fertility regulating methods informed the analysis. RESULTS: A total of 21 IVR users and 29 lubricant users attended focus groups in which they manipulated products in their hands and discussed reactions to product characteristics. Participants used prior product experiences and sensory perceptions of prototype manipulations to inform meanings about product properties and performance for pregnancy, disease prevention, comfort, and perceived efficacy. The meanings derived from product characteristics depended on why the product would be used; a characteristic deemed problematic in one risk context may be considered preferable in another. CONCLUSIONS: Intravaginal product users create narratives that ascribe influence or causality to product characteristics. These meanings, whether correct or incorrect biologically, will shape vaginal product acceptability, use, and effectiveness. IMPLICATIONS: Long-acting and sustained-release drug delivery systems will be part of the multipurpose prevention continuum. Developers must consider how sensory experiences and culturally salient assumptions shape the meanings users make of product design characteristics. Those meanings will ultimately impact use and effectiveness.

Spermicidal and antifertility effects of an imbibing and soluble nonoxynol-9 diaphragm (ISND) in rabbits.

OBJECTIVE: To determine the minimum effective concentration (MEC) of an imbibing and soluble nonoxynol-9 (N-9) diaphragm (ISND) required for immobilisation of all spermatozoa in vitro and in vivo. The speed of semen absorbance, time of ISND to dissolution, and the antifertility effects were also investigated in rabbits. METHODS: In vitro spermicidal tests with ISND were conducted using fresh semen from humans and rabbits. Spermicidal and antifertility effects were observed in vivo after the ISND was placed directly into the vagina of rabbits. RESULTS: The MEC of N-9 required in the ISND to totally immobilise sperm within 20 seconds was 0.15 mg/ml for human sperm, and 0.5 mg/ml for rabbit sperm. The human semen was absorbed into the ISND in 45 minutes; the diaphragm dissolved in the vagina 3.5 hours later. In vivo, in rabbits, the MEC of N-9 required to immobilise sperm within five minutes of mating was 1 mg/kg in the ISND, and 10 mg/kg for the nonoxynol-9 film. The median effective dose of N-9 in the ISND was 1.07 mg/kg, whereas for the film it was 3.30 mg/kg. CONCLUSION: The spermicidal and antifertility activities of a low dose N-9 in the ISND were high, with properties of imbibition and solubility confirmed.

ACIDFORM: a review of the evidence.

OBJECTIVE: 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. STUDY DESIGN: We searched PubMed and Medline for any published literature on ACIDFORM. RESULTS: 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. CONCLUSIONS: 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. IMPLICATIONS: 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.

Combining a synthetic spermicide with a natural trichomonacide for safe, prophylactic contraception.

STUDY QUESTION: Can a specifically acting synthetic spermicide (DSE-37) be combined with a natural microbicide (saponins) for safe, prophylactic contraception? SUMMARY ANSWER: A 1:1 (w/w) combination of DSE-37 and Sapindus saponins can target sperm and Trichomonas vaginalis precisely without any noticeable off-target effects on somatic cells at effective concentrations. WHAT IS KNOWN ALREADY: Broad-spectrum vaginal agents like nonoxynol-9 (N-9) and cellulose sulfate have failed clinically as microbicides due to non-specific off-target effects, whereas agents that specifically target retroviruses have shown promise in clinical trials. DSE-37 and Sapindus saponins, respectively, specifically target human sperm and T. vaginalis in vitro. STUDY DESIGN, SIZE, DURATION: A comprehensive study of efficacy and safety was undertaken using in vitro (human cells) and in vivo (rabbit) models. The 1:1 combination of DSE-37 and Sapindus saponins was based on the in vitro spermicidal and anti-Trichomonal activities of the two components. N-9, the spermicide in clinical use, served as reference control. Free sperm thiols were fluorescently glinted to reveal differences in the targets of the test agents. PARTICIPANTS/MATERIALS, SETTING, METHODS: On/off-target effects were evaluated in vitro against human sperm, T. vaginalis, HeLa, Vk2/E6E7, End1/E6E7 and Lactobacillus jensenii, using standard assays of drug susceptibility, cell viability, flow cytometric assessment of cell apoptosis and qPCR for expression of pro-inflammatory cytokine mRNAs. The spermicidal effect was also recorded live and free thiols on sperm were fluorescently visualized using a commercial kit. In vivo contraceptive efficacy (pregnancy/fertility rates) and safety (vaginal histopathology and in situ immune-labeling of inflammation markers VCAM-1, E-selectin and NFkB) were evaluated in rabbits. MAIN RESULTS AND THE ROLE OF CHANCE: A 0.003% drug 'combination' containing 0.0015% each of DSE-37 and Sapindus saponins in physiological saline irreversibly immobilized 100% human sperm in ∼30 s and eliminated 100% T. vaginalis in 24 h, without causing any detectable toxicity to human cervical (HeLa) cells and Lactobacilli in 24-48 h, in vitro. N-9 at 0.003% exhibited lower microbicidal activity against Trichomonas but failed in spermicidal assays while causing severe toxicity to HeLa cells and Lactobacilli in 12-24 h. The 'combination' of DSE-37 and Sapindus saponins completely prevented pregnancy in rabbits at a vaginal dose of 20 mg (1% in K-Y Jelly), while application of 5% 'combination' in K-Y Jelly for 4 consecutive days caused negligible alterations in epithelial lining of rabbit vagina with only minor changes in levels of inflammation markers. N-9 at a 20 mg vaginal dose prevented pregnancy in 33% animals and a 4-day repeat application of 2% N-9 gel caused severe local toxicity to vaginal epithelium with molecular expression of acute inflammation markers. LIMITATIONS, REASONS FOR CAUTION: The number of animals used for the in vivo efficacy study was limited by the approval of the animal ethics committee. WIDER IMPLICATIONS OF THE FINDINGS: Anti-Trichomonal contraceptives with specifically acting synthetic component and clinically-proven safe natural component may define a new concept in empowering women to control their fertility and reproductive health. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by CSIR-Network Project 'PROGRAM' (BSC0101) and partly by the Ministry of Health and Family Welfare, Government of India (GAP0001). The funding agencies did not play any role in this study and none of the authors had any competing interest(s).

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Spermicide used alone for contraception.

BACKGROUND: Spermicides have been used as contraceptives for thousands of years. Despite this long use, only recently have studies examined the comparative efficacy and acceptability of these vaginal medications. Spermicides contain an active ingredient (most commonly nonoxynol-9) and a formulation used to disperse the product, such as foam or vaginal suppository. OBJECTIVES: This review examined all known randomized controlled trials of a spermicide used alone for contraception. SEARCH METHODS: In August 2013, we searched the following computerized databases for randomized controlled trials of spermicides for contraception: CENTRAL, MEDLINE, POPLINE, LILACS, EMBASE, ClinicalTrials.gov, and ICTRP. For the initial review, we examined the reference lists of trials found as well as those of review articles and textbook chapters. SELECTION CRITERIA: We included any trial of a commercial product used alone for contraception. Each included trial must have provided sufficient information to determine pregnancy rates. DATA COLLECTION AND ANALYSIS: Two authors independently extracted information from the trials identified. We did not conduct a meta-analysis, since most trials had large losses to follow up. We entered the data into tables and presented the results descriptively. MAIN RESULTS: We located reports from 14 trials for the initial review, but have not identified any new trials since then. In the largest trial to date, the gel (Advantage S) containing the lowest dose of nonoxynol-9 (52.5 mg) was significantly less effective in preventing pregnancy than were gels with higher doses of the same agent (100 mg and 150 mg). Probabilities of pregnancy by six months were 22% for the 52.5 mg gel, 16% for the 100 mg dose, and 14% for the 150 mg dose. In the same trial, the three different vehicles with 100 mg of nonoxynol-9 had similar efficacy. Interpretation of these figures is limited, since 39% of participants discontinued the method or were lost from the trial. Few important differences in efficacy emerged in other trials. AUTHORS' CONCLUSIONS: The probability of pregnancy varied widely in reported trials. A gel containing nonoxynol-9 52.5 mg was inferior to two other products tested in the largest trial. Aside from this finding, personal characteristics and behavior of users may be more important than characteristics of the spermicide products in determining the probability of pregnancy. Gel was liked more than the film or vaginal suppository in the largest trial. Spermicide trials have the dual challenges of difficult recruitment and high discontinuation rates; the latter threatens trial validity.

Monitoring vaginal epithelial thickness changes noninvasively in sheep using optical coherence tomography.

OBJECTIVE: High-resolution optical coherence tomography can be used noninvasively to evaluate vaginal morphologic features, including epithelial thickness, to assess this protective barrier in transmission of sexually transmitted infections and to monitor tissue response to topical medications and hormonal fluctuations. We examined the use of optical coherence tomography to measure epithelial thickness noninvasively before and after topical treatment with a drug that causes epithelial thinning. STUDY DESIGN: Twelve female sheep were treated with intravaginal placebo (n = 4) or nonoxynol-9 (n = 8). Vaginal optical coherence tomography images were obtained before and 24 hours after treatment. Four sheep in the nonoxynol-9 group were also examined on days 3 and 7. Vaginal biopsies were obtained on the last examination day. Epithelial thickness was measured in optical coherence tomography images and in hematoxylin and eosin-stained histologic sections from biopsies. Statistical analysis was performed using analyses of variance (significance P < .05). RESULTS: Baseline optical coherence tomography epithelial thickness measurements were similar (85 ± 19 µm placebo, 78 ± 20 µm nonoxynol-9; P = .52). Epithelial thinning was significant after nonoxynol-9 (32 ± 22 µm) compared with placebo (80 ± 15 µm) 24 hours after treatment (P < .0001). In the 4 nonoxynol-9-treated sheep followed for 7 days, epithelial thickness returned to baseline by day 3, and increased significantly on day 7. Epithelial thickness measurements from histology were not significantly different than optical coherence tomography (P = .98 nonoxynol-9, P = .93 hydroxyethyl cellulose). CONCLUSION: Drug-induced changes in the epithelium were clearly detectable using optical coherence tomography imaging. Optical coherence tomography and histology epithelial thickness measurements were similar, validating optical coherence tomography as a noninvasive method for epithelial thickness measurement, providing an important tool for quantitative and longitudinal monitoring of vaginal epithelial changes.

Effectiveness of an optimized benzalkonium chloride gel as vaginal contraceptive: a randomized controlled trial among Chinese women.

BACKGROUND: This study was conducted to evaluate the efficacy, safety and acceptability of a newly developed benzalkonium chloride (BZK) contraceptive gel which was compared to nonoxynol-9 (N-9) gel. STUDY DESIGN: A Phase II, multicenter, randomized, controlled study at three Chinese centers was conducted to compare 120 women who used BZK gel with 120 women who used N-9 gel for 6 months. Contraceptive efficacy was assessed by pregnancy rate, and safety was evaluated by adverse events report, gynecologic examination, Papanicolaou smears, leukorrhea test, and blood and urine tests. The acceptability was assessed through follow-up visit forms and a questionnaire at the 6-month visit. RESULTS: Net cumulative rates in the BZK group at 6 months were as follows: follow-up 100%, terminations 5.1%, pregnancy 1.7%, medical reasons 0% and fear of failure 3.4%. At 6 months, the rates in the N-9 group were as follows: follow-up 99.2%, terminations 9.4%, pregnancy 0.9%, medical reasons 2.5%, fear of failure 3.4% and other personal reasons 2.6%. No significant difference in pregnancy rate and termination rate between the two groups was found (p>.05). Seven cases in the BZK group (5.8%) complained about leukorrhagia and vaginal irritation symptoms (itching and burning) at 6 months, while 16 cases in the N-9 group (13.3%) had similar complaints (p<.05). This significant difference continued to exist until the 6-month visit. The general satisfaction rate for BZK gel use (72.8%) is significantly higher than that for N-9 gel (42.5%). CONCLUSION: The optimized BZK gel is comparable to N-9 gel in terms of contraceptive efficacy and safety, and may be more acceptable to Chinese users.

Decreased cervical epithelial sensitivity to nonoxynol-9 (N-9) after four daily applications in a murine model of topical vaginal microbicide safety.

BACKGROUND: The disappointing clinical failures of five topical vaginal microbicides have provided new insights into factors that impact microbicide safety and efficacy. Specifically, the greater risk for human immunodeficiency virus type 1 (HIV-1) acquisition associated with multiple uses of a nonoxynol-9 (N-9)-containing product has highlighted the importance of application frequency as a variable during pre-clinical microbicide development, particularly in animal model studies. METHODS: To evaluate an association between application frequency and N-9 toxicity, experiments were performed using a mouse model of cervicovaginal microbicide safety. In this model system, changes in cervical and vaginal epithelial integrity, cytokine release, and immune cell infiltration were assessed after single and multiple exposures to N-9. RESULTS: After the initial application of N-9 (aqueous, 1%), considerable damage to the cervical epithelium (but not the vaginal epithelium) was observed as early as 10 min post-exposure and up to 8 h post-exposure. Subsequent daily exposures (up to 4 days) were characterized by diminished cervical toxicity relative to single exposures of like duration. Levels of pro-inflammatory cytokines released into the cervicovaginal lumen and the degree of CD14-positive immune cell infiltration proximal to the cervical epithelium were also dependent on the number of N-9 exposures. CONCLUSIONS: Rather than causing cumulative cervical epithelial damage, repeated applications of N-9 were characterized by decreased sensitivity to N-9-associated toxicity and lower levels of immune cell recruitment. These results provide new insights into the failure of N-9-based microbicides and illustrate the importance of considering multiple exposure protocols in pre-clinical microbicide development strategies.

Phase I randomized safety study of twice daily dosing of acidform vaginal gel: candidate antimicrobial contraceptive.

BACKGROUND: Acidform gel, an acid-buffering product that inactivates spermatozoa, may be an effective topical non-hormonal contraceptive. This study was designed to evaluate the safety of vaginal dosing and effects of Acidform on mucosal immune mediators, antimicrobial properties of genital secretions, and vaginal microbiota. METHODS: Thirty-six sexually abstinent U.S. women were randomized to apply Acidform or hydroxyethylcellulose (HEC) placebo gel twice daily for 14 consecutive days. Safety was assessed by symptoms and pelvic examination. The impact of gel on mucosal immunity was assessed by quantifying cytokines, chemokines, antimicrobial proteins and antimicrobial activity of genital secretions collected by cervicovaginal lavage (CVL) at screening, 2 hours after gel application, and on days 7, 14 and 21. Vaginal microbiota was characterized at enrollment and day 14 using species-specific quantitative PCR assays. RESULTS: The median vaginal and cervical pH was significantly lower 2 hours after application of Acidform and was associated with an increase in the bactericidal activity of CVL against E. coli. However, 65% of women who received Acidform had at least one local adverse event compared with 11% who received placebo (p = 0.002). While there was no increase in inflammatory cytokines or chemokines, CVL concentrations of lactoferrin and interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory protein, were significantly lower following Acidform compared to HEC placebo gel application. There were no significant changes in Lactobacillus crispatus or Lactobacillus jensenii in either group but there was a decrease in Gardnerella vaginalis in the Acidform group (p = 0.08). CONCLUSIONS: Acidform gel may augment mucosal defense as evidenced by an increase in bactericidal activity of genital secretions against E. coli and a decrease in Gardnerella vaginalis colonization. However, Acidform was associated with more irritation than placebo and lower levels of antimicrobial (lactoferrin) and anti-inflammatory (IL-1ra) proteins. These findings indicate the need for additional safety studies of this candidate non-hormonal contraceptive. TRIAL REGISTRATION: ClinicalTrials.gov NCT00850837.

Factors associated with condom use problems during vaginal sex with main and non-main partners.

BACKGROUND: Incorrect condom use is a common problem that can undermine their prevention impact. We assessed the prevalence of 2 condom use problems, breakage/slippage and partial use, compared problems by partnership type, and examined associations with respondent, partner, and partnership characteristics. METHODS: Data were collected at 3-month intervals during a 12-month period (1999-2000) among urban sexually transmitted disease (STD) clinic users. Condom use problems were compared between partnership types using z tests for equality of proportions. Logistic generalized estimating equations modeling accounted for within-participant correlation of repeated measures. RESULTS: Overall 3297 respondents reported 9304 main and 6793 non-main partnerships; condoms were used at least once in 4942 (53.0%) and 4523 (66.6%) of these partnerships, respectively. Condom breakage/slippage was reported during 6.0% of uses (5.1% main, 9.4% non-main) and partial use during 12.5% of uses (12.8% main, 11.5% non-main). The proportion of respondents experiencing any condom use problem in the prior 3 months was higher among main compared with non-main partnerships: 39.1% versus 29.9% had either problem; 22.5% versus 19.0% had breakage/slippage only; 21.8% versus 18.7% had partial use; and 8.7% versus 7.1% had both use problems. In multivariable analysis, factors associated with condom use problems varied by partnership type and respondent sex. The most common predictors of problems across models were sex while high and inconsistent condom use. CONCLUSIONS: This study highlights the diverse set of risk factors for condom use problems at the individual, partner, and partnerships levels.

Contraceptive efficacy and safety of HerbOshield™ vaginal gel in rats.

BACKGROUND: Spermicides represent one of the methods of contraception. The synthetic agents available as spermicides produce severe side effects. Hence, there is a need to replace these agents with safe and effective agents such as plant-based contraceptive agents. STUDY DESIGN: The objective of the present study was to develop and evaluate a stable, safe, effective and easily acceptable contraceptive delivery system containing herbal drug. Efforts were made to evaluate the contraceptive potential of the hydroalcoholic extract from the seeds of Annona squamosa Linn. and the vaginal gel HerbOshield™ containing the extract. RESULTS: Spermicidal effect was evaluated in vitro using healthy human spermatozoa and in vivo in rats. The in vitro results demonstrated that HerbOshield™ vaginal gel is an effective spermicide. At a 100-mg/mL dose, complete immobilization of human spermatozoa was observed within 20 s. None of the treated animals conceived, indicating 100% contraceptive effect as compared to Gynol II, a nonoxynol-9-containing marketed formulation, which showed only 67% contraceptive effect in vivo. HerbOshield™ vaginal gel was found to be safe in animals during a 14-day toxicity study. CONCLUSIONS: HerbOshield™ vaginal gel was found to be safe and effective in rats and could be developed as a potential vaginal contraceptive for future use in humans.

Mucosal integrity and inflammatory markers in the female lower genital tract as potential screening tools for vaginal microbicides.

BACKGROUND: In the female genital tract, vaginal colposcopy, endometrial mucosal integrity and inflammatory mediators are potential in vivo biomarkers of microbicide and contraceptive safety. STUDY DESIGN: A randomized, blinded crossover trial of 18 subjects comparing effects of nonoxynol-9 vaginal gel (Gynol II; putative inflammatory gel), hydroxyethyl cellulose gel (HEC; putative inert gel) and no gel exposure on endometrial and vaginal epithelial integrity and endometrial and vaginal inflammatory markers [interleukin (IL) 1ß, IL-6, IL-8, MCP-1, MIP-1α, MIP-1ß, RANTES, tumor necrosis factor α, IL-1RA, IL-10, SLPI). RESULTS: Gynol II was associated with more vaginal lesions. No endometrial disruptions were observed across conditions. In the vagina, RANTES (p=.055) and IL-6 (p=.04) were higher after HEC exposure than at baseline. In the endometrium, IL-1ß (p=.003) and IL-8 (p=.025) were lower after Gynol II cycles than after no gel. CONCLUSIONS: Gynol II and HEC may modulate inflammatory markers in the vagina and endometrium. How these changes relate to infection susceptibility warrants further study.

Safety studies of sperm agglutinating factor produced by Staphylococcus aureus as a vaginal contraceptive: in vivo studies.

Sperm agglutinating factor (SAF) isolated from Staphylococcus aureus when applied at concentration 10 µg before mating completely prevented conception in the mouse. The objective of the present study was to evaluate its safety, as safety is an important concern to be addressed before a compound is selected for contraceptive use. Our results showed that SAF has a very high safety profile. Vaginal application of SAF at 10 µg to the mouse for 14 consecutive days caused no systemic toxicity and vaginal irritation as indicated by lack of effect on organ weights and histology. Moreover, no adverse effect was observed on the subsequent reproductive capability, perinatal outcome and growth and development of the offspring. SAF (10 µg) did not irritate the skin or penile mucosa. Oral administration of 2 mg/kg body weight of SAF did not show any toxicity to reproductive and non-reproductive organs. Therefore, SAF with spermicidal activity and lack of toxicity may have the potential to become the active ingredient of a vaginal contraceptive.

Functional attenuation of human sperm by novel, non-surfactant spermicides: precise targeting of membrane physiology without affecting structure.

BACKGROUND: We have attempted to identify structural, physiological and other targets on human sperm vulnerable to the spermicidal action of two novel series of non-detergent molecules, reported to irreversibly immobilize human sperm in <30 s, apparently without disrupting plasma membrane. METHODS: Three sperm samples were studied. Scanning and transmission electron microscopy were used to assess structural aberrations of sperm membrane; plasma membrane potential and intracellular pH measurements (fluorometric) were used to detect changes in sperm physiology; reactive oxygen species (ROS, fluorometric) and superoxide dismutase activity (colorimetric) were indicators of oxidative stress; and sperm dynein ATPase activity demonstrated alterations in motor energy potential, in response to spermicide treatment. Post-ejaculation tyrosine phosphorylation of human sperm proteins (immunoblotting) was a marker for functional integrity. RESULTS: Disulfide esters of carbothioic acid (DSE compounds) caused complete sperm attenuation at > or =0.002% concentration with hyper-polarization of sperm membrane potential (P < 0.001), intracellular alkalinization (P < 0.01), ROS generation (P < 0.05) and no apparent effect on sperm (n = 150) membrane structure. Isoxazolecarbaldehyde compounds required > or =0.03% for spermicidal action and caused disrupted outer acrosomal membrane structure, depolarization of membrane potential (P < 0.001), intracellular acidification (P < 0.01) and ROS generation (P < 0.01). Detergent [nonoxynol-9 (N-9)] action was sustainable at > or =0.05% and involved complete breakdown of structural and physiological membrane integrity with ROS generation (P < 0.001). All spermicides caused functional attenuation of sperm without inhibiting motor energetics. Unlike N-9, DSE-37 (vaginal dose, 200 microg) completely inhibited pregnancy in rats and vaginal epithelium was unchanged (24 h,10 mg). CONCLUSIONS: The study reveals a unique mechanism of action for DSE spermicides. DSE-37 holds promise as a safe vaginal contraceptive. CDRI Communication No. 7545.

Adherence and its measurement in phase 2/3 microbicide trials.

Adherence optimization and measurement have emerged as critically challenging issues for clinical trials of topical microbicides. Although microbicide trials have routinely collected adherence data, their utilization in trial design, implementation, and interpretation has been inconsistent. Drawing on data-driven presentations from several focused meetings, this paper synthesizes lessons from past microbicide trials and provides recommendations for future trials of microbicide and other HIV prevention technologies. First, it describes four purposes for adherence data collection, with particular attention to intention-to-treat versus adherence-adjusted analyses for determining effectiveness. Second, the microbicide field's experiences with adherence measures and data collection modes are discussed, including the strengths and weaknesses of various options and approaches for improving measurement. Then, several approaches to optimizing trial participants' adherence are presented. The paper concludes with a set of recommendations for immediate use or further research.