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Many sexually active, reproductive-aged persons capable of becoming pregnant use some method of contraception. To expand options for those desiring birth control, new choices include a vaginal ring, transdermal patch, progestin-only pill, and spermicide. Compared with currently available methods, additional technologies that are highly effective, easy to use, cost efficient, and well-tolerated lay on the horizon. During contraceptive counseling, patient choice, and reproductive autonomy should remain paramount.

Current contraceptive methods come with a number of drawbacks, including low efficacy, in the case of commercial contraceptive gels, and a reduction in the quality of sexual intercourse, in the case of condoms. Adding pharmacologically-active agents to contraceptive gels holds the potential to improve sexual experience, and hardbor safety and hygiene. In this study, we fabricated a Carbomer-based contraceptive gel consisting of three agents: tenofovir, gossypol acetate, and nitroglycerin (TGN), with pH adjusted to 4.5 (to be compatible with the vagina). In vitro, the gossypol component of the contraceptive gel proved to be a significantly effective spermicide. When the concentration of gossypol acetate was 10 mg/ml, the spermicidal ability reached 100% after 30s. In addition, tenofovir in the gel significantly inhibited lentiviral transfection efficiency in cell-containing media. In 6 pairs of rats, the gel successfully prevented all females from conceiving after successful mating. Moreover, increased sexual frequency and enhanced erection, which were promoted by the nitroglycerin in the components, were observed in male rats that had the gel applied to their penises. This novel TGN contraceptive gel yielded a higher contraceptive success rate than that of the commercial contraceptive gel (Contragel®). In addition, it has the added benefits to prevent sexually transmitted diseases and improve male libido and erection function during sexual intercourse. Combining three FDA-approved and marketed agents together, our trifunctional TGN gel has a great potential for further translation and commercialization., Graphical abstract Image 1, Highlights • Our novel TGN contraceptive gel yielded a higher contraceptive success rate than that of a commercial product (Contragel®). • The TGN gel inhibits viral infection and shows great potential to prevent sexually transmitted diseases. • Male libido and erection function are enhanced after topical application of the TGN gel. • Combining three FDA-approved agents together, our TGN gel has a great potential for translation and commercialization.

Vaginal mucosal surfaces naturally offer some protection against sexually transmitted infections (STIs) including Human Immunodeficiency Virus-1, however topical preventative medications or vaccine designed to boost local immune responses can further enhance this protection. We previously developed a novel mucosal vaccine strategy using viral vectors integrated into mouse dermal epithelium to induce virus-specific humoral and cellular immune responses at the site of exposure. Since vaccine integration occurs at the site of cell replication (basal layer 100-400 micrometers below the surface), temporal epithelial thinning during vaccine application, confirmed with high resolution imaging, is desirable. In this study, strategies for vaginal mucosal thinning were evaluated noninvasively using optical coherence tomography (OCT) to map reproductive tract epithelial thickness (ET) in macaques to optimize basal layer access in preparation for future effective intravaginal mucosal vaccination studies. Twelve adolescent female rhesus macaques (5-7kg) were randomly assigned to interventions to induce vaginal mucosal thinning, including cytobrush mechanical abrasion, the chemical surfactant spermicide nonoxynol-9 (N9), the hormonal contraceptive depomedroxyprogesterone acetate (DMPA), or no intervention. Macaques were evaluated at baseline and after interventions using colposcopy, vaginal biopsies, and OCT imaging, which allowed for real-time in vivo visualization and measurement of ET of the mid-vagina, fornices, and cervix. P value ≤0.05 was considered significant. Colposcopy findings included pink, rugated tissue with variable degrees of white-tipped, thickened epithelium. Baseline ET of the fornices was thinner than the cervix and vagina (p

Objectives To evaluate the spermicidal efficacy of non-hormonal vaginal gel in vitro and in a post-coital test, and to evaluate its contraceptive efficacy in Canadian women of childbearing age. Methods We conducted single-centre trial to assess spermicidal and contraceptive efficacy of vaginal gel. Participants were healthy, sexually active women aged 18–49 years and their regular male sexual partners (30 couples). Measured outcomes included effect of vaginal gel on sperm motility in vitro, its effect on sperm in a post-coital test, and its effect on pregnancy prevention over 3 months. Results For in vitro spermicidal effect, 98% and 67% of sperm were immotile in the presence of the gel with sodium lauryl sulfate (gel-SLS) and gel alone, respectively. For the post-coital test, 99% and 93% of sperm were immotile in the presence of gel-SLS and gel alone, respectively. In the second part of trial, a total of 410 instances of vaginal intercourse in 95 menstrual cycles were protected (during 3-month period of gel-SLS use before each sexual intercourse with probability of 24 conceptions prevented according to Wilcox's table). Four women became pregnant during the study period; 2 during unprotected vaginal intercourse around the time of ovulation, and 2 attributed to user failure. Conclusion Based on our results, the vaginal gel demonstrated important spermicidal and contraceptive effect. A larger phase III contraceptive efficacy trial is warranted. The vaginal gel may represent a non-hormonal spermicide/contraceptive option for women.

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.This paper describes key properties of Amphora, including its acid-buffering abilities, viscosity, stability, bioadhesiveness, and tolerability.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.

The aim of our study was to evaluate the effects of ozonised olive oil (OOO) on human sperm in vitro.Human sperm was incubated with OOO for 20 s in vitro. The lowest concentration that completely immobilised all the sperm in 20 s without subsequent recovery of motility was recorded as the minimum effective concentration (MEC). The effects of OOO at MEC on human sperm viability, mitochondrial and acrosomal status, DNA integrity and transmission electron microscopy were observed.Our findings demonstrate that OOO dose-dependently inhibits sperm motility. The MEC of OOO for 100% sperm immobilisation in 20 s was 6 μg/ml. Further experiments showed that sperm ultrastructure, function and DNA integrity were significantly affected after treatment with 6 μg/ml OOO in vitro.OOO has spermicidal potential and may be explored as a promising vaginal contraceptive agent.

A study was performed to investigate the effect of an intravaginally administered antimycotic, an antibiotic, and a spermicide plus the co‐usage of tampons on the pharmacokinetics (PK) of levonorgestrel (LNG) and anastrozole (ATZ) administered as an intravaginal ring (IVR) releasing 1050 μg ATZ per day and 40 μg LNG per day. In this parallel‐group, randomized, open‐label study, healthy premenopausal women received an IVR as the main treatment. Comedications were administered on 3 consecutive evenings during treatment with IVR on days 9–11 (group A, 400 mg miconazole; group B, 100 mg clindamycin; group C, 75 mg nonoxynol‐9); tampon co‐usage (group D) was performed on days 20–23. The primary PK parameter was the average plasma concentration (Cav,ss) of ATZ and LNG at defined intervals, mainly prior to, during, and up to 7 days after the start of comedication. Fifty‐two subjects were included, and at least 11 subjects per group completed the treatments. Overall, the medications and comedications were safe and well tolerated. Very similar ATZ and LNG plasma levels were observed across all groups. The calculated ratios of Cav,ss confirmed the absence of PK interactions because all relevant point estimates and 90% confidence intervals were within the range of 0.800–1.250, which is typically used in bioequivalence studies. These results demonstrate the absence of PK interactions between ATZ/LNG released from IVR and the tested antibiotic, antimycotic, spermicide, and tampons. Therefore, no restrictions for the use of the IVR are needed to continue the clinical program intended to treat endometriosis symptoms.

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth., Ureaplasma parvum is often isolated from intrauterine infections, which are associated with 40% of preterm births. Here, Pavlidis et al. present a mouse model of ascending U. parvum infection that resembles human disease, and show that mild cervical damage promotes intrauterine infection, inflammation and preterm birth.

Finger root plant (Kaempferia pandurata ROXB) is one of the medicinal plants. Aside from being a spice, based on research, finger root plant can be used as a cough medicine, mouth ulcer, laxative, appetite enhancer, analgesic, antipyretic, anti-inflammatory, antioxidant, antibiotic, antitumor, antibacterial, abortivum, resorption, increase breast milk production, and affect the fetal weight of mice. The compounds found in the finger root plant are essential oils, starch, resin, tannins, saponins, flavonoids, pinostrolerin, and alipinetin. Plants that contain saponins, flavonoids, and phenols mostly have spermicide or sperm immobilization effects. Based on this, the utilization of finger root rhizomes may have an impact on the reproductive organs. Until now, there are only few studies on the effect of finger root rhizomes on reproductive organs, especially as anti-fertility agent. The use of natural ingredients as anti-fertility agent has smaller side effects than synthetic chemical agents. This study aimed to determine the effect of decoction of finger root rhizomes simplicia on sperm quality of male mice. This research is an experimental research with a Randomized Block Design. Mice used were male mice, aged 10-12 weeks with a weight of 28-32 g. The concentrations used were 0%, 5%, 7.5%, 10%, 12.5% and 15%. Finger root was administrated by gavage method for 18 days. The results showed that decoction of finger root rhizomes affected Balb/C mice (Mus musculus) testis, which tended to reduce seminiferous tubule diameter and thickness of spermatogenic cells.

dl-Mandelic acid (MA), an alpha-hydroxycarboxylic acid, has been widely used as an intermediate of pharmaceutical and fine chemicals. Here, we evaluated the sperm-immobilizing activity of MA and its safety profiles. Spermatozoon motility was assessed by computer-aided sperm analysis, the integrity of the plasma membrane and. mitochondrial potential was assessed using fluorescein isothiocyanate-pisum sativum agglutinin and JC-1, respectively. The local tolerance of the MA-containing gel formulation was evaluated using a rabbit vaginal irritation test. We found that MA inhibited sperm motility and movement patterns in a concentration-dependent manner. Within 20 s, MA-induced spermatozoa immobilization occurred with a minimum effective concentration and a median effective concentration of 0.86 and 0.54 mg/mL, respectively. Plasma membrane disruptions of MA-treated spermatozoa were relatively mild, but mitochondrial depolarization occurred. Histopathological examination showed that MA exposure did not exert obvious effects on the integrity of spermatozoa membrane structures and only caused slight irritation to the rabbit vaginal epithelium. The vaginal irritation scores of the vehicle control and the nonoxynol −9 gel control groups were 1.38 ± 0.65 and 7.88 ± 1.67, respectively (p < 0.01), whereas those of the MA gel groups at 10, 20, and 40 mg/mL were 1.69 ± 1.04, 2.98 ± 0.77, and 4.35 ± 1.04 with p values of >0.05, >0.05, and

OBJECTIVES: To elucidate the effects of the intravaginal ring, oral contraceptive pill (OCP), and spermicide plus condom on women’s sexual experiences through an in-depth understanding of the physical characteristics of these contraceptive methods. METHOD: We conducted qualitative in-depth interviews with women (aged 18–45 years) who used up to three contraceptive methods (intravaginal ring, OCP, and spermicide plus condom). Women completed in-depth interviews after each 3-month use period. We used a summarized matrix framework and thematic content analysis to explore how each method affected participants’ sexual experiences. RESULTS: Sixteen women completed interviews, yielding 33 transcripts. Women reported physical effects on their sexual experiences while using the intravaginal ring and spermicide plus condom. The OCP was often discussed as lacking these physical effects. Discussion themes included product administration (e.g., navigating intravaginal ring removal) and physical product awareness (e.g., spermicide as a lubricant). From these experiences, women often altered and individualized their use and subsequent opinions of the contraceptive method. CONCLUSIONS: The range of contraceptive effects on women’s sexual experiences shape their use and opinions of the product, leading to either increased motivation and consistent use or poor adherence and discontinuation. Awareness of these individualized experiences can help providers better understand and guide their patients towards successful contraceptive use.

Background: For biotechnological application, selected lactic acid bacteria strains belonging to the genera Lactobacillus (Lb) are proposed as an alternative to the antibiotics for the prevention and treatment of urogenital tract infections. Objectives: Isolating and selecting vaginal lactobacilli strains for probiotic use based on their technological and probiotic aptitudes. Materials and Methods: The vaginal isolates were examined for their essential characteristics as the potential probiotic such as low pH tolerance, bile-salt and simulated human intestinal fluid (SIF) resistance, adhesion to the vaginal epithelial cells (VECs), aggregation and coaggregation, surface hydrophobicity, antimicrobial activity, acid production, antibiotic resistance, and resistance to spermicides. The best strain was identified by PCR. Results: From 70 lactobacilli isolates and according to the 16 rDNA sequences, isolates B6 and B10 showed the closest homology (99%) to the Lb. gasseri and Lb. plantarum respectively. They produced hydrogen peroxide (H2O2), tolerant to acid, bile, simulated human intestinal fluid, present a strong adhesion, highest percentages of aggregation, and antibacterial activity. These strains are resistant to the spermicide and actively acidify the growth medium. Conclusions: Strains Lb. plantarum B10 and Lb. gasseri B6 have a strong potential probiotic confirming their value as a tool for prevention against urinary and vaginal infections.

Objectives: We aimed to evaluate the antifertility activity and vaginal irritation effects of tideglusib in vivo using rabbit models and to evaluate the cytotoxical effects of tideglusib to sperm, vaginal cells and vaginal bacteria (L. acidophilus) in vitro. Study design: We treated female rabbits with vaginal tideglusib 1 mM, nonoxynol-9 (N-9) or vehicle control (Poloxamer 407). In experiment 1, we sacrificed females (n = 6 each) after 10 days of daily administration and assessed vaginal histological changes using Eckstein irritation score. In experiment 2, females (n = 9 each) received estradiol benzoate to induce ovulation 24 h prior to vaginal treatment followed by introduction of a fertile male. These females underwent necropsy at the 21st day to assess pregnancy status. In experiment 3, we used an HTM-TOX IVOS sperm motility analyzer and scanning electron microscopy (SEM) to evaluate the effect of tideglusib on human sperm samples. In experiment 4, we evaluated the effect of tideglusib on lactobacillus and vaginal cell growth in vitro. Results: The total irritation score of tideglusib vs. N-9 was 3.4 ± 2.07 vs. 7.8 ± 3.82, p

STUDY QUESTION: Do the truncated LL-37 peptides, GI-20 and GF-17, have spermicidal activity and microbicidal effects on the sexually transmitted infection (STI) pathogen Neisseria gonorrhoeae with equivalent potency to LL-37? SUMMARY ANSWER: GI-20 and GF-17 exhibited spermicidal effects on both mouse and human sperm as well as microbicidal action on N. gonorrhoeae with the same efficacy as LL-37. WHAT IS KNOWN ALREADY: The antimicrobial peptide LL-37 exerts microbicidal activity against various STI pathogens as well as spermicidal effects on both mouse and human sperm. STUDY DESIGN, SIZE, DURATION: Spermicidal activities of GI-20 and GF-17 were evaluated in vitro in mouse and human sperm and in vivo in mice. Finally, in vitro antimicrobial effects of LL-37, GI-20 and GF-17 on an STI pathogen, N. gonorrhoeae were determined. All experiments were repeated three times or more. In particular, sperm samples from different males were used on each experimental day. PARTICIPANTS/MATERIALS, SETTING, METHODS: The plasma membrane integrity of peptide-treated sperm was assessed by cellular exclusion of Sytox Green, a membrane impermeable fluorescent DNA dye. Successful mouse in vitro fertilization was revealed by the presence of two pronuclei in oocytes following co-incubation with capacitated untreated/peptide-pretreated sperm. Sperm plus each peptide were transcervically injected into female mice and the success of in vivo fertilization was scored by the formation of 2–4 cell embryos 42 h afterward. Reproductive tract tissues of peptide pre-exposed females were then assessed histologically for any damage. Minimal inhibitory/bactericidal concentrations of LL-37, GI-20 and GF-17 on N. gonorrhoeae were determined by a standard method. MAIN RESULTS AND THE ROLE OF CHANCE: Like LL-37, treatment of sperm with GI-20 and GF-17 resulted in dose-dependent increases in sperm plasma membrane permeabilization, reaching the maximum at 18 and 3.6 μM for human and mouse sperm, respectively (P < 0.0001, as compared with untreated sperm). Mouse sperm treated with 3.6 μM GI-20 or GF-17 did not fertilize oocytes either in vitro or in vivo. Moreover, reproductive tract tissues of female mice pre-exposed to 3.6 μM GI-20 or GF-17 remained intact with no lesions, erosions or ulcerations. At 1.8–7.2 μM, LL-37, GI-20 and GF-17 exerted bactericidal effects on N. gonorrhoeae. LARGE SCALE DATA: N/A LIMITATIONS, REASONS FOR CAUTION: Direct demonstration of the inhibitory effects of GI-20 and GF-17 on human in vitro and in vivo fertilization cannot be performed due to ethical issues. WIDER IMPLICATIONS OF THE FINDINGS: Like LL-37, GI-20 and GF-17 acted as spermicides and microbicides against N. gonorrhoeae, without adverse effects on female reproductive tissues. With lower synthesis costs, GI-20 and GF-17 are attractive peptides for further development into vaginal spermicides/microbicides. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Canadian Institutes of Health Research (MOP119438 and CCI82413 to N.T.) and NIH (R01 AI105147 to G.W.). There are no competing interests to declare.

In an ongoing effort to discover an effective topical dual-function non-surfactant contraceptive vaginal microbicide a novel series of 22-disulfanediylbis(3-(substituted-1-yl)propane-21-diyl) disubstituted-1-carbodithioates were designed by using a bioisosterism approach. Thirty-three compounds were synthesized and interestingly most demonstrated multiple activities: they were found to be spermicidal at a minimal effective concentration of 1-0.001 % trichomonacidal against drug-susceptible and resistant Trichomonas strains at minimal inhibitory concentration (MIC) ranges of 10.81-377.64 and 10.81-754.14 muM respectively and fungicidal at MIC 7.93-86.50 muM. These compounds were also found to be non-cytotoxic to human cervical (HeLa) epithelial cells and vaginal microflora (Lactobacilli) in vitro. The most promising compound 22-disulfanediylbis(3-(pyrrolidin-1-yl)propane-21-diyl)dipyrrolidine-1-carbodi thioate (5) exhibited spermicidal activity 15-fold higher than that of the marketed spermicide Nonoxynol-9 (N-9) and also demonstrated microbicidal potency. To identify common structural features required for spermicidal activity a 3D-QSAR analysis was carried out as well as in vivo efficacy studies and fluorescent labeling studies to determine the biological targets of compound 5. (c) 2015 WILEY-VCH Verlag GmbH & Co. KGaA Weinheim.

The growing population and health-care burden (due to STIs and HIV) imposes a particular economic crisis over resource-poor countries. Thus a novel approach as vaginal microbicides emerges as integrated tool to control both population and anti-STIs/HIV. Our continued efforts in this field led to the synthesis of fifteen N-alkyl/aryl-4-(3-substituted-3-phenylpropyl) piperazine-1-carbothioamide (12–26) derivatives as topical vaginal microbicides which were evaluated for anti-Trichomonas, spermicidal, antifungal and reverse transcriptase (RT) inhibitory activities. All compounds were also tested for preliminary safety through cytotoxicity assays against human cervical cell line (HeLa) and the vaginal flora, Lactobacillus. Docking studies were performed to gain an insight into the binding mode and interactions of the most promising compound 12 [oxo derivative], comprising of reverse transcriptase (RT) inhibitory (72.30%), spermicidal (MEC 0.01%), anti-Trichomonas (MIC 46.72 μM) and antifungal (MIC 9.34–74.8 μM) activities, along with its hydroxyl (17) and O-alkylated 4-trifluoromethylphenoxy (22) derivative, with similar activities. The stability of compound 12 in simulated vaginal fluid (SVF) and its preliminary in vivo pharmacokinetics performed in female NZ-rabbits signifies its clinical safety in comparison to marketed spermicide Nonoxynol-9.

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 ± 1.21, those of the blank control and B07 gel groups were 2.17 ± 0.76 and 4.00 ± 0.89, respectively, which were within the clinically acceptable range (8). The proportion of inflammatory cells and CD45

Background In our previous work, several piperazine derived bis(dialkylaminethiocarbonyl) disulfides and disulfide esters of dithiocarbamic acid have been synthesized and evaluated for their spermicidal and microbicidal efficacy. These studies have provided some promising compounds for developing a dually active vaginal microbicidal contraceptive which is under pre-clinical stage. Objective The main objective of this study was the design synthesis and biological evaluation of bis(dialkylaminethiocarbonyl) disulfides (4-15) and 2,2'-disulfanediylbis (3-(substituted-1-yl) propane-2,1-diyl) disubstituted-1-carbodithioates (19-28) as non-surfactant molecules capable of eliminating Trichomonas vaginalis as well as irreversibly immobilizing 100% human sperm promptly. Method Spermicidal, anti-trichomonas, cytotoxicity and biocompatibility study of the synthesized compounds was done as per the reported methodologies. Result Among bis(dialkylaminethiocarbonyl) disulfides (4-15, Table 1), compound 4 (MEC 0.02 mM) was found to be the most desirable for spermicidal activity as it was 40 times more active than Nonoxynol-9 (N-9), and also active against Trichomonas vaginalis (MIC 0.02 &1.10 mM). 2, 2'-disulfanediylbis (3-(substituted- 1-yl) propane-2, 1-diyl) disubstituted-1-carbodithioates (19-28, Table 2), and compounds (19, 22, 23, and 24 MEC 0.05 mM) were sixteen times more active than N-9 with promising Trichomonacidal activity. Conclusion This study suggested that the disulfide linkage alone and dithiocarbamate along with disulfide group within the same chemical entity impart the desired multiple activities of compounds.

Introduction The vaginal flora of healthy adult women of reproductive age group constitutes predominantly Lactobacilli which inhibits the growth of other microorganisms (by maintaining acidic pH). The vaginal microflora is altered in favour of anaerobes in women using Intra Uterine Contraceptive Device (IUCD). Also, it can cause morphologic changes in both squamous and endocervical columnar cells. Similarly, the prevalence of vaginal lactobacilli is reduced among women using diaphragm-spermicide or spermicide alone. Aim To study the effects of different contraceptive methods on cervical cytology and vaginal flora. Materials and methods Two years prospective study included 120 women of reproductive age group using barrier, tubal ligation, IUCDs, Oral Contraceptive Pills (OCPs) and injectable methods of contraception and a control group including 60 women not using any contraceptive. Cervical and vaginal smears were obtained. Cervical smears were reported using the Bethesda system and Gram stained vaginal smears were scored using Nugent scoring. SPSS (Statistical Package for the Social Sciences) software for Windows Version 19.0 and test of significance applied was Chi-square test. Results The most common contraception used was barrier (68.3%) followed by tubal ligation (14.2%), IUCD (9.2%), OCPs (6.6%) and injectable (1.7%). The presenting complaints were pain lower abdomen (46.7%) followed by menstrual complaints (22.5%). Epithelium showed reactive changes (45%) followed by metaplasia (25%), koilocytotic change (5%), cytolytic effect (5%) and satellitosis (4.2%). Women showed normal flora in 51.7%, altered in 30% and bacterial vaginosis in 18.3%. Conclusion Cervico-vaginal changes were more frequent in contraceptive users as compared to the control group.

Presently available contraceptives are mostly hormonal or detergent in nature with numerous side effects like irritation lesion inflammation in vagina alteration of body homeostasis etc. Antimicrobial peptides with spermicidal activity but without adverse effects may be suitable alternatives. In the present study spermicidal activity of a cationic antimicrobial peptide VRP on human spermatozoa has been elucidated. Progressive forward motility of human spermatozoa was instantly stopped after 100 microM VRP treatment and at 350 microM all kinds of sperm motility ceased within 20 seconds as assessed by the Sander-Cramer assay. The spermicidal effect was confirmed by eosin-nigrosin assay and HOS test. VRP treatment (100microM) in human spermatozoa induced both the intrinsic and extrinsic pathways of apoptosis. TUNEL assay showed VRP treatment significantly disrupted the DNA integrity and changed the mitochondrial membrane permeability as evident from MPTP assay. AFM and SEM results depicted ultra structural changes including disruption of the acrosomal cap and plasma membrane of the head and midpiece region after treatment with 350 microM VRP. MTT assay showed after treatments with 100 microM and 350 microM of VRP for 24 hrs a substantial amount of Lactobacillus acidophilus (about 90% and 75% respectively) remained viable. Hence VRP being a small synthetic peptide with antimicrobial and spermicidal activity but tolerable to normal vaginal microflora may be a suitable target for elucidating its contraceptive potentiality. This article is protected by copyright. All rights reserved.

A series of seventeen morpholin/piperidin-1-yl-carbamodithioate (3-19) were synthesized as topical vaginal microbicidal spermicides. The synthesized compounds were evaluated for their anti-Trichomonas activity against MTZ susceptible and resistant strains along with their spermicidal and antifungal potential. All the synthesized compounds were assessed for their safety through cytotoxic assay against human cervical cell line (HeLa) and compatibility with vaginal flora, Lactobacillus. The study identified eleven dually active compounds with apparent safety. The plausible mode of action of these compounds was through sulfhydryl binding, confirmed via reduction in available free thiols on human sperm. The most promising compound 9 significantly inhibited (P

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.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.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.The spermicidal and antifertility activities of a low dose N-9 in the ISND were high, with properties of imbibition and solubility confirmed.

Nonoxynol-9 (N-9), a microbicidal spermicide, has been in use as an over-the-counter contraceptive since the 1960s. A detailed account of its pharmacokinetic profile using highly sensitive detection method has not been reported yet. We developed and validated a rapid, selective and sensitive high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method for N-9 detection in plasma and simulated vaginal fluid. The analytes were quantified using reverse phase Thermo Accucore C18 (150 mm × 4.6mm, 5 μm) column with isocratic elution using acetonitrile: 0.1% formic acid in triple distilled water (90:10, v/v) as mobile phase. The ionization was optimized using ESI (+) and selectivity was achieved by tandem mass spectrometric analysis using MRM transition, m/z 617.4→133.2 for N-9 and m/z 180.1→138.1 for phenacetin. The method was linear over the range 0.195-100 ng/mL. The method was accurate and precise with intra-batch and inter-batch accuracy (% bias) of less than ± 15% and precision (% CV) of

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.

Prostate-specific antigen (PSA) is a biomarker of recent semen exposure. There is currently only limited information on whether topical vaginal products affect PSA assays. We investigated this question using various dilutions of several vaginal products (lubricants and spermicides) and the Abacus ABAcard for PSA detection.Pooled semen controls and various dilutions of nonoxynol-9 (N9), carboxymethyl cellulose (CMC), Replens, Gynol 2, K-Y jelly, Astroglide, Surgilube, combined with pooled semen dilutions, were tested for PSA using the Abacus ABAcard.N9 (2% with saline) and CMC did not appear to affect the results of testing with the ABAcard, but not all semen dilutions were tested. The other products (including Replens and Gynol, which is 2% N9 with propylene glycol, K-Y, Astroglide and Surgilube) at some of the dilutions tested either affected or gave invalid results with PSA testing using the ABAcard. Both Gynol 2 and K-Y at 1:10 dilution gave false-positive results.Some vaginal products affect PSA results obtained by using the semiquantitative ABAcard. In vivo confirmation is necessary to further optimize PSA detection when topical vaginal products are present.

Sexually transmitted infections (STIs) and unplanned pregnancies have serious effects on the reproductive health of women. The present study was undertaken with a view to develop an effective means of prevention. The microbicidal and contraceptive potential of cationic peptides from frog's skin, namely, dermaseptin S4 and its derivatives were investigated in vitro.: STUDY DESIGN Different bacterial and fungal strains were resorted to for determining the antimicrobial activity of the new compounds. The spermicidal activities of the latter were assessed using normal human semen samples, and their toxic effects were identified in a HeLa culture.All S4 derivatives elicited concentration-dependent spermicidal and antimicrobial activities at microgram concentrations. The highest levels recorded for both types of activity were displayed by K4K20S4, and the lowest levels were exhibited by D4D20S4 and S4(5-28). Cytotoxicity assays revealed that some of these compounds were significantly safer than nonoxynol-9 (N-9).The ability of these peptides to instantaneously kill human sperm and STI pathogens at low concentrations indicates that their application as active ingredients in vaginal contraceptive preparations could induce considerably better effects than N-9.

Background: Over-the-counter (OTC) feminine hygiene products come with little warning about possible side effects. This study evaluates in-vitro their effects on Lactobacillus crispatus , which is dominant in the normal vaginal microbiota and helps maintain a healthy mucosal barrier essential for normal reproductive function and prevention of sexually transmitted infections and gynecologic cancer. Methods: A feminine moisturizer (Vagisil), personal lubricant, and douche were purchased OTC. A topical spermicide (nonoxynol-9) known to alter the vaginal immune barrier was used as a control. L. crispatus was incubated with each product for 2 and 24h and then seeded on agar for colony forming units (CFU). Human vaginal epithelial cells were exposed to products in the presence or absence of L. crispatus for 24h, followed by epithelium-associated CFU enumeration. Interleukin-8 was immunoassayed and ANOVA was used for statistical evaluation. Results: Nonoxynol-9 and Vagisil suppressed Lactobacillus growth at 2h and killed all bacteria at 24h. The lubricant decreased bacterial growth insignificantly at 2h but killed all at 24h. The douche did not have a significant effect. At full strength, all products suppressed epithelial viability and all, except the douche, suppressed epithelial-associated CFU. When applied at non-toxic dose in the absence of bacteria, the douche and moisturizer induced an increase of IL-8, suggesting a potential to initiate inflammatory reaction. In the presence of L. crispatus , the proinflammatory effects of the douche and moisturizer were countered, and IL-8 production was inhibited in the presence of the other products. Conclusion: Some OTC vaginal products may be harmful to L. crispatus and alter the vaginal immune environment. Illustrated through these results, L. crispatus is essential in the preservation of the function of vaginal epithelial cells in the presence of some feminine hygiene products. More research should be invested toward these products before they are placed on the market. Keywords: Lactobacillus; L. crispatus; cytokines; Interleukin-8; Nonoxynol-9; vaginal microbiota; vaginal epithelial colonization; mucosal immunity (Published: 25 February 2013) Citation: Microbial Ecology in Health & Disease 2013, 24 : 19703 - http://dx.doi.org/10.3402/mehd.v24i0.19703

The concurrent increases in global population and sexually transmitted infection (STI) demand a search for agents with dual spermicidal and microbicidal properties for topical vaginal application. Previous attempts to develop the surfactant spermicide, nonoxynol-9 (N-9), into a vaginal microbicide were unsuccessful largely due to its inefficiency to kill microbes. Furthermore, N-9 causes damage to the vaginal epithelium, thus accelerating microbes to enter the women's body. For this reason, antimicrobial peptides (AMPs), naturally secreted by all forms of life as part of innate immunity, deserve evaluation for their potential spermicidal effects. To date, twelve spermicidal AMPs have been described including LL-37, magainin 2 and nisin A. Human cathelicidin LL-37 is the most promising spermicidal AMP to be further developed for vaginal use for the following reasons. First, it is a human AMP naturally produced in the vagina after intercourse. Second, LL-37 exerts microbicidal effects to numerous microbes including those that cause STI. Third, its cytotoxicity is selective to sperm and not to the female reproductive tract. Furthermore, the spermicidal effects of LL-37 have been demonstrated in vivo in mice. Therefore, the availability of LL-37 as a vaginal spermicide/microbicide will empower women for self-protection against unwanted pregnancies and STI.

In the course of the validation of a new component of the prostate-specific antigen (PSA) SemiQuant Cassette Test marketed by Seratec(®) , a false-positive reaction was observed when testing samples collected from the surface of unused, lubricated condoms. A variety of personal lubricants and condoms were tested to determine the frequency of the false positive, as well as its potential source. Samples were extracted in both water and the manufacturer-provided buffer, and the test was performed according to the manufacturer's suggested protocol. The false positive was observed intermittently, but occurred consistently with samples containing nonoxynol-9, a strong detergent utilized as a spermicide. The reaction may be attributable to the combination of latex and nonoxynol-9. Because of the unreliability of the test to confirm the presence of PSA in samples collected from condoms, the PSA cassette is an unsuitable method for confirming the presence of seminal fluid in condoms.

The spermicide nonoxynol-9 is actually a complex mixture of dozens of closely related amphiphilic compounds, and the chemical properties of this assortment significantly hamper its characterization by GC-MS. The inability to perform routine GC-MS testing on nonoxynol-9 has limited its evidentiary value in forensic casework, which relies heavily on this technique for analysis. A disturbing trend in sexual assault is the use of condoms by assailants, to avoid leaving behind DNA evidence that can connect a perpetrator to a victim. This observation necessitates the development of alternative methods for the analysis of trace evidence that can show causal links between a victim and a suspect. Detection of lubricants associated with sexual assault is one such way to establish this connection. The development of GC-MS methods that permit facile detection of both nonoxynol-9 alone and nonoxynol-9 extracted from other complex matrices that have potential as trace evidence in sexual assault is reported. A detection limit of 2.14 μg of nonoxynol-9 is demonstrated, and a detailed mass spectral profile that elaborates on what is known of its structure is provided.

WHI-05 (5-bromo-6-methoxy-5,6-dihydro-3’-azidothymidine-5’-(p-methoxyphenyl) methoxyalaninyl phosphate, CAS 213982-93-5) is a highly promising antiviral and spermicidal agent with clinical potential as a vaginal contraceptive which can prevent the sexual transmission of AIDS. In this study, the contraceptive activity of WHI-05 in rabbits was evaluated. Exposure of semen to WHI-05 at the time of artificial insemination inhibited pregnancy and embryo implantation by 90 %. Intravaginal application of 2 % WHI-05 containing gel also inhibited the pregnancy rate by 90 %. WHI-05 had no side effects for the offspring of rabbits who became pregnant despite WHI-05.

Preservatives are present in numerous multidose eyedrops and provide the sterility of the solution against bacteria and fungi. However, numerous studies have shown their toxicity for the ocular surface, particularly in long-term treatments. The most widely used preservative in eyedrops is benzalkonium chloride. This quaternary ammonium acts as a detergent, antiseptic, disinfectant, fungicide, bactericide, and spermicide. Its use on the ocular surface therefore has significant consequences. Indeed, the preservatives are pro-apoptotic, pro-inflammatory and they cause the dissolution of the lachrymal film. The prolonged administration of one or several eye drops containing preservatives induces changes in the superficial structures (conjunctiva, cornea) as well as in deeper structures (trabecula, lens). The least severe symptoms are irritation and discomfort, including sensation of a foreign body, itching, or burning sensations. However, more severe side effects have been described, such as chronic inflammation of variable intensity or the progressive development of fibrosis with higher risk of failure after glaucoma filtering surgery. Ideally, preservative-free eyedrops should be recommended, or at least a reduction of the number of instilled preserved eyedrops should be considered. All these strategies could increase patient comfort, quality of life, and compliance, with better outcome at the time of filtering surgery.

Chemical contraceptives mainly known as spermicides are one of the oldest types of contraceptives. The industrial revolution facilitated new developments, and they became a leading and widespread method. However, their use declined in the second half of the 20th century, and came under focus again only with the upsurge of sexually transmitted infections (STIs). The effectiveness of spermicides depends on the users' compliance and pregnancy rates vary widely: from 6/100 woman-year (with perfect use) to 26/100 woman-year (with typical use). Preparations consist of two components: an excipient (foam, cream, jelly, soluble film, suppository or tablet); and a chemical agent with spermicidal properties (acidic compound, microbicidal agent, detergent). The most widely used active agent has been the surface active (detergent) nonoxynol-9 (N-9). Based on their mode of action (surfactant effect of detergents, enzymatic action of microbicides on cell metabolism) spermicides were thought to provide protection against STIs including HIV. Recent studies have, however, shown that detergents may actually increase the risk. Because of this, there is an urgent need for a suitable non-detergent spermicide, and research should focus on developing new compounds to replace N-9 and other agents having similar undesired effects. This paper reviews the latest studies reporting results on these recent developments.

Background Women may become pregnant while using contraceptives. Commonly used contraceptives containing spermicides may or may not be associated with an increased occurrence of structural birth defects. Study Design Utilizing data from the National Birth Defects Prevention Study, we assessed maternal reports of spermicide and male condom use 1 to 3 months following conception among case ( n =11,050) and control ( n =4723) mothers. We assessed the association between spermicide use and 27 types of birth defects and that between condom use and 32 types of birth defects. Results Maternal spermicide use during the first 3 months following conception was associated with a significant increase in the occurrence of only 1 of 27 birth defects, perimembranous ventricular septal defects (adjusted odds ratio=2.40, 95% confidence interval=1.25���4.62). There was no significant association between maternal use of male condoms during the first 3 months following conception and any of 32 types of birth defects. Conclusions The increased occurrence of perimembranous ventricular septal defects among spermicide users may be real or may be a chance finding. Overall, the findings are consistent with those of most previous studies that observed no increased risk for birth defects among spermicide users.

The spermicidal activity of menfegol-coated condoms was investigated. Menfegol (P-menthanyl-phenyl-polyxyethylene [88] ether) showed strong spermicidal activity at 0.5 mg/ml and higher concentration. Semen was ejaculated directly into menfegol-coated condoms (20 mg/condom) or uncoated condoms. Immediately after ejaculation sperm motility and viability were examined. In the menfegol-coated condoms sperm motility was completely suppressed and viable sperm were observed. In the uncoated condoms most of the sperm were alive although their motility was almost suppressed. These results indicate that the menfegol-coated condom represents a new birth control method in which the contraceptive efficacy of the condom is enhanced by the spermicidal activity of menfegol. (authors modified) (summary in GER)

BACKGROUND Rational synthesis of novel structures resulted in two unique molecules (DSE-36 and DSE-37, disulphide esters of carbothioic acid) that killed sperm 25 times more strongly and with a precisely targeted action than nonoxynol-9 (N-9). We examine the effects of DSE-36 and DSE-37 on human spermatozoa versus HeLa cells to establish specificity and safety compared with N-9. METHODS AND RESULTS At spermicidal EC(100) (20 microg/ml) DSE-36 and DSE-37 killed 100% sperm in

OBJECTIVE: Opinions remain divided concerning the potential for additional water-based lubricant to reduce condom breaks and slips. We sought to explore impact of externally applied additional lubrication on condom failure rates among regular users in stable heterosexual relationships. GOAL: To compare condom failure rates with and without additional spermicide. STUDY DESIGN: Couples randomized to use up to 70 condoms alone (control) or with additional spermicide (intervention) with midpoint crossover. Couple demographic and failure risk data collected at baseline. Follow ups at three and six months recorded condom failure events spermicide acceptability side-effects and adverse events. Condom failure rates were compared using an intention to treat analysis. RESULTS: Altogether 12530 condoms were used by 145 couples completing the trial There were 45/6463:0.70% (95% CI 0.51%-0.93%) clinical and nonclinical failures in the additional spermicide arm compared to 111/6067:1.83% (95% CI 1.51%-2.20%) during the control arm. The clinical condom failure rate was 0.53% (95% CI 0.41%-0.66%) with 19 (0.31%: 95% CI 0.18%-0.43%) during the additional spermicide arm compared to 46 (0.77%: 95% CI 0.56%-0.99%) during the control arm. Couples experienced significantly lower total (P = 0.017) and clinical (P = 0.042) condom failure rates during the additional spermicide arm. Furthermore additional spermicide significantly reduced clinical failures among the 101 couples whod experienced a previous condom failure (P = 0.002). There were 22 urinary tract infections equally divided between the control and additional spermicide arms however 10 of the 12 genital irritation episodes occurred with additional spermicide (P = 0.021). CONCLUSIONS: Additional water-based external lubricant significantly reduced condom failures despite low failure rates among this stable experienced group of condom users. Our results suggest that this may be a useful supplement to condom use particularly among couples who experienced condom failures previously.

Background This study was conducted to compare the effectiveness of a new, single-size silicone contraceptive diaphragm used with either spermicide [2% nonoxynol-9 (N-9)] or lubricant in preventing sperm from penetrating midcycle cervical mucus. Study design A crossover postcoital test (PCT) in healthy, sexually active women not at risk for pregnancy due to tubal occlusion was conducted. Couples had a baseline PCT without a device to verify normal fertility parameters. Qualified couples underwent up to two test cycles using the SILCS diaphragm with a metal spring. A subgroup of couples underwent a third test cycle with the SILCS polymer spring diaphragm used with N-9 gel. Results Fifteen couples completed a baseline cycle and were randomized to order of study gel. Of these, 14 couples completed a baseline cycle and at least one test cycle, 12 couples completed a baseline cycle and two test cycles and 8 couples completed a third test cycle with the polymer spring prototype. Sperm was detected in the vaginal pool in all completed test cycles. The SILCS metal spring diaphragms used with N-9 gel reduced the average number of progressively motile sperm per high power field in the cervical mucus from a baseline of 12.5 to 0, while use of this device with lubricant reduced the number to 0.5. The SILCS polymer spring diaphragm used with N-9 performed the same as the metal spring used with N-9. Conclusion The SILCS diaphragm used with N-9 gel performed well. It is likely that the SILCS diaphragm will give acceptable results in a contraceptive effectiveness study but that adjunctive use of a chemical barrier such as N-9 gel will be necessary for it to be most effective.

Background This analysis was undertaken to compare the effect of the different dosages and formulations of spermicides containing nonoxynol-9 (N-9) on cervical cytology. Study Design A randomized trial was conducted at 14 sites in the United States to evaluate the effectiveness and safety of five spermicides containing N-9. This Papanicolaou smear analysis included the data from all participants who provided two Papanicolaou smear samples: at admission and after discontinuation of the product. The effects of the spermicides were evaluated by comparing the rates of alteration of cervical cytology between five study groups. Results A total of 640 women were included in this analysis. The majority of the study participants (>85%) had no change of their baseline Papanicolaou smear result. The rates of alteration of cervical cytology were similar among women using the three gels containing the different doses of N-9 and three different formulations containing the same dose of N-9. Our analysis found no association between alteration of cervical cytology and duration or frequency of use of the five study spermicides. Conclusions Exposure to different formulations and doses of spermicides containing N-9 is unlikely to influence cervical cytology.

Nonoxynol-9 (N-9) is the most active ingredient in commercially available spermicidal products in the United States. There are many applications of cyclodextrin inclusion complexes (CD-ICs), but there are no reported studies investigating the formation of and controlled release from a N-9 spermicide-CD-IC. We have successfully formed the inclusion compound between N-9 and α-CD using a solution-heating technique. The N-9-α-CD-IC was characterized by Fourier Transform infrared spectroscopy, nuclear magnetic resonance spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and wide angle X-ray diffraction observations. Silicone elastomer (SILASTIC MDX4-4210) film embedded with crystalline N-9-α-CD-IC was prepared and evaluated for its efficacy in the controlled release of N-9 spermicide against bovine sperm. Silicone elastomer with N-9-α-CD-IC was as successful in reducing the motility and viability of bovine spermtazoa as silicone elastomer swollen with an equivalent amount of neat N-9. The permeability of the flexible silicone elastomer apparently enables the N-9 spermicide to diffuse from its embedded inclusion complex crystals to contact, immobilize, and kill bovine sperm cells. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007

There is an urgent clinical need to research novel methods of fertility control that are also protective against sexually transmitted diseases (STDs) such as the human immunodeficiency virus (HIV) or Chlamydia. The most obvious way to generate such a dual-purpose contraceptive method would be to develop safe, effective spermicides that were also active against a wide range of pathogenic organisms. The currently available formulations such as nonoxynol-9, gramicidin and benzalkonium chloride are effective spermicides but are toxic to the vaginal epithelium and do not provide protection against STDs. Over 60 agents are in clinical trials as potentially safer topical spermicides and/or microbicides. Compounds that have reached this stage of development include acid buffers, detergents, dendrimers, non-nucleoside reverse transcriptase inhibitors and anionic polymers. In addition, a number of potential spermicides/microbicides are the subject of preclinical investigation, including beta-cyclodextrin, cyanovirin, porphyrins, cyclotriazadisulfonamides, dermaseptins, short-interfering RNA (siRNA) and HIV antibodies. The chemical principles underlying these disparate approaches and potential avenues for future investigation are discussed.

Purpose Aqueous decoction of Chenopodium album seeds (CAD) was assessed for its sperm-immobilizing and contraceptive efficacy in laboratory mammals. Method Spermicidal efficacy was evaluated in vitro by a modified Sander���Cramer test. The mode of spermicidal action was assessed by (a) supravital and double fluoroprobe staining of sperm, (b) hypoosmotic swelling tests and (c) transmission electron microscopy. Contraceptive efficacy was evaluated by intrauterine and vaginal application of CAD in rats and rabbits, respectively, followed by their mating and evaluation of pregnancy outcomes. Results The minimum effective concentration of CAD that induced instantaneous immobilization of rat spermatozoa in vitro was 2 mg/mL. The mechanism of CAD action involved disintegration of sperm plasma membrane and dissolution of acrosomal cap causing sperm death. Fertilization of oocytes and establishment of implantation were prevented in the uterine horn that was administered with CAD, while these events occurred unhindered in the untreated contralateral side. In rabbit, intravaginal application of CAD significantly blocked the establishment of pregnancy. Conclusion CAD possesses appreciable spermicidal potential, which may be explored as an effector constituent of vaginal contraceptive.

Trichomoniasis and candidiasis are amongst the most common morbidity-causing reproductive tract infections, generally treated by Metronidazole and Fluconazole respectively. Poor vaginal efficacy, drug-resistance and non-spermicidal nature limit their use as topical microbicidal contraceptives. Bis(dialkylaminethiocarbonyl)disulfides (4-38) were designed as dually active, non-surfactant molecules capable of eliminating Trichomonas vaginalis and Candida strains as well as irreversibly immobilizing 100% human sperm instantly, at doses non-cytotoxic to human cervical epithelial cells and vaginal microflora in vitro. Compounds 12, 16, 17 were fifty times more active than nonoxynol-9, OTC vaginal spermicide, and compounds 12 and 17 have shown remarkable in vivo activity in rabbit model. Most promising compound 17 has shown promise for further development as a double-edged vaginal microbicide due to their improved activity and safety along with notable in vivo trichomonicidal activity. Role of disulfide group was established by loss of spermicidal activity on chemical modifications (39-56). These disulfides might be targeting thiol groups present over cell membrane of human sperm and Trichomonas as shown by fluorescence labeling of free thiols.

Objective To determine the feasibility of using quantitative changes in vaginal permeability to small molecules as a measure of candidate microbicide toxicity. Study design Controlled, open-labeled, prospective study. Seven healthy women received a single vaginal dose of hydroxyethylcellulose gel (HEC), nonoxynol-9 (N-9) or K-Y Jelly. Each gel was radiolabeled with a small molecule ( 99m Tc-DTPA) followed by 12-h blood and urine collection. Pharmacokinetic (PK) parameters of 99m Tc-DTPA were calculated to compare the impact of each gel on vaginal permeability. Each woman served as her own control. The Friedman test with post hoc Wilcoxon test was used to detect differences among the gels. Results Vaginal permeability of 99m Tc-DTPA was highest for the N-9 radiolabel. N-9 plasma area under the concentration curve was 2.7-fold higher (p=.04), and peak concentration was threefold higher (p=.04) compared to HEC. There were no significant PK parameter differences between HEC and K-Y Jelly or between N-9 and K-Y Jelly. Cumulative dose-adjusted median (interquartile range) 12-h timed urine gamma activity was 66.70×10 −4 μCi (27.90–152.00) following HEC dosing, 103.00×10 −4 μCi (98.20–684.00) following N-9 gel dosing and 20.30×10 −4 μCi (11.10–55.90) following K-Y gel dosing. The differences between urine HEC and K-Y Jelly (p=.047) and between N-9 and K-Y Jelly (p=.016) were statistically significant. Conclusions It is feasible to measure differences in vaginal permeability among vaginal gels using a radiolabeled small molecule, though there are permeability differences that require a nuanced understanding of gel composition to interpret the results. Implications Establishing the safety of both vehicle and active pharmaceutical ingredient is an essential task in microbicide development, to be determined as soon as possible. This study suggests that a combination of microbicide toxicity assessments, that is, cervicovaginal permeability, inspection and histopathology, may need to be studied simultaneously.

BACKGROUND The design, synthesis, characterization and evaluation of a novel series of non-detergent spermicides has led to the discovery of two unique molecules (DSE-36 and DSE-37) that were approximately 25 times more potent spermicides than nonoxynol-9 (N-9). METHODS Normal human spermatozoa were used to assess the spermicidal activity (Sander-Cramer Assay), the effect on sperm-membrane integrity [hypo-osmotic swelling test (HOST)], supravital staining and scanning electron microscopy (SEM) and the induction of apoptosis [fluorescein isothiocyanate (FITC) Annexin-V and JC-1 labelling using flow cytometry] by the new class of compounds. HeLa and Lactobacillus cultures were used to assess the cytotoxicity of compounds and their compatibility to normal vaginal flora, respectively. RESULTS Compounds DSE-36 and DSE-37 exhibited a strong spermicidal activity [minimum effective concentration (MEC) = 0.002%], which was approximately 25 times more potent than that of N-9 and Sapindus saponins (MEC = 0.05%). As compared with surfactants, DSE-36 and DSE-37 were found to be safer at MEC towards the growth and survival of Lactobacilli and HeLa cells in vitro and to have a milder effect on sperm plasma membrane. At EC(50) both induced apoptosis in sperm cells as characterized by increased labelling with Annexin-V and decreased polarization of sperm mitochondria. CONCLUSION Preliminary studies have revealed that in sharp contrast to the non-specific surfactant action of N-9, DSE-36 and DSE-37 have a highly potent, mechanism-based, detrimental action on human sperm. The unique ability of these non-detergent molecules to selectively kill sperm and spare Lactobacilli and HeLa cells at MEC values much lower than that required for N-9 indicates their potential as superior ingredients for formulation into microbicidal contraceptives.

The objective of this study was to evaluate the long-term stability of the antiretroviral spermicide WHI-07 (5-bromo-6-methoxy-5,6-dihydro-3'-azidothymidine-5'-(p-bromophenyl)-methoxyalaninyl phosphate) in a polymer-based microemulsion. The recovery and stability of WHI-07 in gel-microemulsion was examined by a validated high-performance liquid chromatography (HPLC) method. The stability was examined over a period of 24 weeks at 3 controlled temperatures (4 degrees C, 25 degrees C, and 40 degrees C). The recovery of the prodrug from 0.5% to 2.0% WHI-07-loaded gel-microemulsion was 99.8%. HPLC analysis revealed that a 2% WHI-07-loaded gel-microemulsion stored at room temperature and cold temperatures for 24 weeks retained90% of the prodrug, whereas those stored at 40 degrees C maintained 90% of initial WHI-07 for at least 10 weeks. The observed stability of WHI-07 in gel-microemulsion is of great importance for its widespread utility in various climatological conditions.

Background ACIDFORM is a microbicidal and contraceptive candidate with strong buffering capacity. Methods 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. Results 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. Conclusions 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.

Aim To compare the effectiveness of an acid-buffering formulation gel (ACIDFORM) with metronidazole gel in the treatment of symptomatic bacterial vaginosis (BV). Methods After a confirmed diagnosis of BV according to the criteria established by Nugent and Amsel, 30 nonpregnant women were enrolled in a randomized, double-blind clinical study. The women were randomly assigned to receive either 5 g ACIDFORM gel (n = 13) or 10% metronidazole gel (n = 17) intravaginally once daily for five consecutive days. Participants were evaluated in two follow-up visits (7–12 days and 28–35 days after treatment). Therapeutic success was defined as the presence of less than three of Amsel's criteria. If three or more criteria were present at first or second follow-up visit, the woman was excluded from the study and treated orally with metronidazole. Nugent scores were recorded at each visit but these were not used to define cure. Results At the first follow-up visit, 15 (88%) of the women in the metronidazole group were cured compared with only three (23%) in the ACIDFORM group (P