Berberine-fluconazole microparticle-based combination therapy to treat candidiasis infections.

AIM: This study aims to incorporate alginate microparticles containing berberine and fluconazole into two different types of pharmaceutical formulations, to subsequently evaluate the antifungal activity against Candida albicans. METHODS AND RESULTS: Alginate microparticles containing BBR (berberine) and FLU (fluconazole) were produced by the spray-drying technique, characterized and incorporated in two pharmaceutical formulations, a vaginal cream and artificial saliva. Broth microdilution, checkerboard, time-kill curve, and scanning electron microscopy were carried out to determine the antifungal effects of BBR and FLU against C. albicans. The minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) values of free BBR were 125 µg ml-1. Synergism between BBR and FLU was demonstrated by a fractional inhibitory concentration index (FICI) = 0.0762. The time-kill curve for the combination BBR + FLU showed a more pronounced decrease in fungal growth in comparison to free drugs, and an antibiofilm effect of BBR occurred in the formation and preformed biofilm. CONCLUSION: Alginate microparticles containing BBR and FLU were obtained and incorporated in a vaginal cream and artificial saliva. Both formulations showed good stability, antifungal effects, and organoleptic characteristics, which suggest that BBR-FLU microparticles in formulations have potential as antifungal therapy.

ROS mediated anticandidal efficacy of 3-Bromopyruvate prevents vulvovaginal candidiasis in mice model.

Candidal infections, particularly vulvovaginal candidiasis (VVC), necessitate effective therapeutic interventions in clinical settings owing to their intricate clinical nature and elusive understanding of their etiological mechanisms. Given the challenges in developing effective antifungal therapies, the strategy of repurposing existing pharmaceuticals has emerged as a promising approach to combat drug-resistant fungi. In this regard, the current study investigates molecular insights on the anti-candidal efficacy of a well-proven anticancer small molecule -3-bromopyruvate (3BP) against three clinically significant VVC causing Candida species viz., C. albicans, C. tropicalis and C. glabrata. Furthermore, the study validates 3BP's therapeutic application by developing it as a vaginal cream for the treatment of VVC. 3BP exhibited phenomenal antifungal efficacy (killing >99%) with minimum inhibitory concentrations (MIC) and minimum fungicidal concentrations (MFC) of 256 µg/mL against all tested Candida spp. Time killing kinetics experiment revealed 20 min as the minimum time required for 3BP at 2XMIC to achieve complete-killing (99.9%) in all Candida strains. Moreover, the ergosterol or sorbitol experiment explicated that the antifungal activity of 3BP does not stem from targeting the cell wall or the membrane component ergosterol. Instead, 3BP was observed to instigate a sequence of pre-apoptotic cascade events, such as phosphatidylserine (PS) externalization, nuclear condensation and ROS accumulations, as evidenced by PI, DAPI and DCFH-DA staining methods. Furthermore, 3BP demonstrated a remarkable efficacy in eradicating mature biofilms of Candida spp., achieving a maximum eradication level of 90%. Toxicity/safety profiling in both in vitro erythrocyte lysis and in vivo Galleria mellonella survival assay authenticated the non-toxic nature of 3BP up to 512 µg/mL. Finally, a vaginal cream formulated with 3BP was found to be effective in VVC-induced female mice model, as it significantly decreasing fungal load and protecting vaginal mucosa. Concomitantly, the present study serves as a clear demonstration of antifungal mechanistic action of anticancer drug -3BP, against Candida species. This finding holds significant potential for mitigating candidal infections, particularly VVC, within healthcare environments.

Effect of Chamomile Vaginal Gel on the Sexual Function in Postmenopausal Women: A Double-Blind Randomized Controlled Trial.

BACKGROUND: Female sexual dysfunction (FSD) is a common complaint among postmenopausal women, which is largely because of the genitourinary syndrome in these women (GSM). AIM: Considering the phytoestrogenic effects of chamomile, the present study was primarily aimed to investigate the effect of chamomile vaginal gel on the sexual function of postmenopausal women. The side effects of these drugs were evaluated as a secondary outcome of the study. METHODS: This randomized double-blind clinical trial and placebo-controlled study was conducted on postmenopausal women with sexual dysfunction (FSFI ≤26.55). To this aim, 96 postmenopausal women were randomly assigned into three groups (n = 32 each) including women receiving (i) chamomile vaginal gel 5%, (ii) conjugated estrogen vaginal cream, and (iii) placebo vaginal gel, for 12 weeks (ie, every night in the first 2 weeks, and 2 nights per week in the next 10 weeks, each night 1 g was used). The sexual function was measured using female sexual function index (FSFI) before and after the intervention. Data analysis was performed by chi-square, one-way ANOVA, descriptive statistics, analysis of covariance (ANCOVA), and paired t test using SPSS software version 22. P < .05 was considered statistically significant. OUTCOMES: The main study outcome measure was evaluate the effects of vaginal administration of chamomile gel in comparison with conjugated estrogen cream and placebo gel on postmenopausal FSD using the FSFI. RESULTS: The findings showed that chamomile vaginal gel in compared to placebo vaginal gel caused a significant improvement in all six sexual function domains and the total FSFI score (effect size = +2.9 [95% CI, +2.1 to +3.6], P < .001). Also, there was no significant difference between the chamomile vaginal gel and conjugated estrogen vaginal cream groups in terms of the total score and all sub-domains of sexual function with the exception of orgasm (effect size = +0.13 [95% CI, -0.36 to +0.63], P = .02) and sexual satisfaction (effect size = 0 [95% CI, -0.49 to +0.49], P = .04). Two women in the chamomile group and one in the placebo group experienced a burning sensation (P = .345). CLINICAL IMPLICATIONS: This treatment can be considered as a treatment option for postmenopausal women with sexual dysfunction who have contraindications to the use of hormone therapy. STRENGTHS & LIMITATIONS: This study is the first study to investigate the effectiveness of chamomile vaginal gel on sexual function in postmenopausal women. However, in this study, treatment duration was 12 weeks and no follow up was performed beyond this time CONCLUSION: Based on the results of this study, the use of vaginal chamomile gel improved sexual function in postmenopausal women. Bosak Z, Iravani M, Moghimipour E, et al. Effect of Chamomile Vaginal Gel on the Sexual Function in Postmenopausal Women: A Double-Blind Randomized Controlled Trial. J Sex Med 2022;19:983-994.

Evaluation of the novel vaginal contraceptive agent PPCM in preclinical studies using sperm hyaluronan binding and acrosome status assays.

BACKGROUND: Polyphenylene carboxymethylene (PPCM) sodium salt is a promising multipurpose technology for prevention of both sexually transmitted infections (STIs) and pregnancy. In preclinical studies, PPCM has demonstrated significant (1) antimicrobial activity against several important viral and bacterial pathogens and (2) contraceptive activity associated with premature acrosome loss. OBJECTIVE: To further evaluate a vaginal antimicrobial compound as a contraceptive agent in preclinical studies utilizing a repurposed hyaluronan binding assay (HBA). MATERIALS AND METHODS: Semen samples containing either neat semen or washed spermatozoa were treated with increasing concentrations of PPCM or calcium ionophore A23187 (positive control). Sperm inactivation was measured by two methods: (1) double acrosome staining (AS), and (2) a hyaluronan binding assay (HBA® ). Percentage of inactivated sperm was compared between untreated control sperm and those treated with PPCM or A23187. RESULTS: PPCM had a significant (p < 0.05) and dose-dependent effect on sperm inactivation in both assays, with HBA detecting a higher proportion of inactivated sperm than AS. PPCM did not affect sperm motility and exhibited equivalent responses in the neat and washed samples. DISCUSSION: Both HBA and AS confirmed that spermatozoa were rapidly inactivated at PPCM concentrations likely present in the vagina under actual use conditions and in a time-frame comparable to in vivo migration of spermatozoa out of seminal plasma into cervical mucus. CONCLUSION: PPCM vaginal gel may provide contraceptive protection as well as help with STI prevention. HBA may be a sensitive and much needed biomarker for sperm activity in future contraceptive development.

Bioadhesive-Thermosensitive In Situ Vaginal Gel of the Gel Flake-Solid Dispersion of Itraconazole for Enhanced Antifungal Activity in the Treatment of Vaginal Candidiasis.

The poor solubility of itraconazole (ITZ) has limited its efficacy in the treatment of vaginal candidiasis. Accordingly, the improvement of ITZ solubility using a solid dispersion technique was important to enhance its antifungal activity. Besides, as the purpose of this research was to develop local-targeting formulations, bioadhesive-thermosensitive in situ vaginal gel combined with the gel-flake system was found to be the most suitable choice. To obtain optimum solubility, entrapment efficiency, and drug-loading capacity, optimization of solid dispersion (SD) and gel-flake formulations of ITZ was performed using a composite central design. The results showed that the optimized formulation of SD-ITZ was able to significantly enhance its solubility in both water and simulated vaginal fluid to reach the values of 4.211 ± 0.23 and 4.291 ± 0.21 mg/mL, respectively. Additionally, the optimized formulation of SD-ITZ gel flakes possessed desirable entrapment efficiency and drug-loading capacity. The in situ vaginal gel containing SD-ITZ gel flakes was prepared using PF-127 and PF-68, as the gelling agents, with the addition of hydroxypropyl methylcellulose (HPMC) as the mucoadhesive polymer. It was found that the obtained in situ vaginal gel provided desirable physicochemical properties and was able to retain an amount of more than 4 mg of ITZ in the vaginal tissue after 8 h. Importantly, according to the in vivo antifungal activity using infection animal models, the incorporation of the solid dispersion technique and gel-flake system in the formulation of the bioadhesive-thermosensitive in situ vaginal gel led to the most significant decrease of the growth of Candida albicans reaching <1 log colony-forming units (CFU)/mL or equivalent to <10% of the total colony after 14 days, indicating the improvement of ITZ antifungal activity compared to other treated groups. Therefore, these studies confirmed a great potential to enhance the efficacy of ITZ in treating vaginal candidiasis. Following these findings, several further experiments need to be performed to ensure acceptability and usability before the research reaches the clinical stage.

Efficacy of a Coriolus versicolor-Based Vaginal Gel in Women With Human Papillomavirus-Dependent Cervical Lesions: The PALOMA Study.

OBJECTIVE: The aim of the study was to evaluate the efficacy of Papilocare, a Coriolus versicolor-based vaginal gel, in repairing human papillomavirus (HPV)-related low-grade cervical lesions. METHODS: The study is a multicenter, open-label, randomized, parallel-group, watchful waiting approach-controlled trial involving 91 HPV-positive women with low-grade Pap smear alterations and consistent colposcopy. RESULTS: The percentage of patients with normal Pap smear and concordant colposcopy 3 and 6 months after receiving treatment (78.0% and 84.9%) was significantly higher than without treatment (54.8% and 64.5%), especially in high-risk HPV patients (79.5% and 87.8% vs 52.0% and 56.0%). At 6-month visit, overall HPV clearance was achieved by a greater number of patients receiving treatment (59.6%) compared with those without treatment (41.9%), especially high-risk HPV ones (62.5% vs 40.0%). The cervical re-epithelization score was significantly higher with treatment (mean = 4.5) than without (mean = 4.1). Compared with baseline, perceived stress decreased in the treatment group (from 21.1 to 19.0) and increased in the control group (from 17.7 to 20.7). A total of 7 possible or probable treatment-related adverse events were reported, most of them (n = 6) being mild or moderate in severity. CONCLUSIONS: Treatment with Papilocare has demonstrated a better clinical benefit than the conventional watchful waiting approach in clinical practice for total and high-risk HPV patients in terms of its efficacy to treat HPV-related cervical lesions and to clear all HPV strains after a single 6-month period. It has demonstrated an adequate safety and tolerability and confers additional benefits such as higher re-epithelization, stress reduction, and high treatment adherence.

Correlation between detergent activity and anti-herpes simplex virus-2 activity of commercially available vaginal gels.

OBJECTIVE: Herpes simplex virus-2 (HSV-2) infections are almost exclusively sexually transmitted. The presence of vaginal gels during sexual activity may have a significant positive or negative impact on viral transmission. Therefore we investigated three off-the-shelf vaginal lubricants and one pH restoring gel to evaluate their impact on HSV-2 replication. RESULTS: HeLa cells were infected with untreated virions and virions incubated with the particular gels. The accumulation of viral genomes was monitored by quantitative PCR (qPCR) method at 24 h post infection. Two of the tested gels had no significant effect on HSV-2 replication at the maximum applied concentration, while two had a strong inhibitory effect (~ 98% reduction of replication). The replication inhibitory effect was observed at various multiplicity of infection (MOI 0.4-6.4) and the two inhibitory gels were also capable of inhibiting the HSV-2 induced cytopathic effect on HeLa cells. The surface tension decreasing activity-an indication of detergent activity-was strongly correlated with the anti-HSV-2 activity of the gels (R2: 0.88). Our results indicate that off-the-shelf vaginal gels have a markedly different anti-HSV-2 activity that may influence HSV-2 transmission.

Replens prevents preterm birth by decreasing type I interferon strengthening the cervical epithelial barrier.

PROBLEM: A breakdown of the cervical epithelial barrier has been associated with preterm cervical remodeling. It is unknown if Replens, the vehicle for vaginal progesterone, alters cervical epithelial junctional proteins impacting cervical remodeling and preterm birth. METHOD OF STUDY: E17 CD-1 pregnant mice received an intrauterine injection of saline or lipopolysaccharide (LPS). Effect of intravaginal Replens given on day E16 and on E17 coincident with LPS was tested. A second experiment determined if an antibody to the interferon receptor (IFNaR) blocked the effects of LPS. Mice were killed after six hours, the preterm birth rate was recorded, and the serum and cervices were collected for analysis. Additionally, the epithelial cell barrier was assessed using an in vitro permeability assay. RESULTS: Replens decreased the rate of LPS-induced preterm birth within six hours, from 87.5% to 37.5% (P < .005). LPS + IFNaR antibody decreased the rate of preterm birth or vaginal bleeding compared to LPS + control antibody mice, 43.8% vs 87%, respectively (P < .01). E-Cadherin in the mouse serum was increased by LPS, an effect mitigated by treatment with Replens (P < .0001) or the IFNaR antibody (P < .01). Replens + LPS decreased the expression of IFN-ß (P < .01). The anti-IFNaR, as well as Replens, decreased the expression of MMP13 (P < .05) compared to LPS mice. Replens also prevented the LPS-induced increase in permeability (P < .001). CONCLUSION: Replens prevents preterm birth by decreasing the interferon-induced upregulation of MMP13 and the degradation of the cell adhesion protein E-Cadherin. Further studies are needed to determine if Replens can be useful as treatment for preterm birth.

Managing vulvovaginal atrophy after breast cancer.

Cancer treatment may result in loss of ovarian function through surgical removal of the ovaries, chemotherapy or radiation. While menopausal symptoms, such as hot flushes, night sweats, sleep disturbance, memory concerns and mood issues can be extremely bothersome to some women going through menopause naturally, women who undergo an induced menopause usually experience more sudden and severe symptoms. Pain and vaginal dryness can occur whether a woman has a sexual partner or not. In women with breast cancer, the aetiology of impaired sexual functioning, and lowered sexual desire, is often multifactorial, and may be related to physical and/or psychological reasons. Pain and vaginal dryness in women without a history of breast cancer can usually be safely treated with vaginal estrogens, in the form of a cream, pessary or ring, and simple lubricants or vaginal moisturisers. Safe usage of vaginal estrogen replacement therapy in breast cancer patients has not been studied within randomised clinical trials of long duration; the guidelines below reflect a clinical consensus.

Rhodanine derivatives as potent anti-HIV and anti-HSV microbicides.

Although highly active antiretroviral therapies (HAART) remarkably increased life expectancy of HIV positive people, the rate of novel HIV-1 infections worldwide still represent a major concern. In this context, pre-exposure prophylaxis (PrEP) approaches such as vaginal microbicide gels topically releasing antiretroviral drugs, showed to have a striking impact in limiting HIV-1 spread. Nevertheless, the co-presence of other genital infections, particularly those due to HSV-1 or 2, constitute a serious drawback that strongly limits the efficacy of PrEP approaches. For this reason, combinations of different compounds with mixed antiviral and antiretroviral activity are thoroughly investigated Here we report the synthesis and the biological evaluation of a novel series of rhodanine derivatives, which showed to inhibit both HIV-1 and HSV-1/2 replication at nanomolar concentration, and were found to be active also on acyclovir resistant HSV-2 strains. The compounds showed a considerable reduction of activity in presence of serum due to a high binding to serum albumin, as determined through in vitro ADME evaluations. However, the most promising compound of the series maintained a considerable activity in gel formulation, with an EC50 comparable to that obtained for the reference drug tenofovir. Moreover, the series of compounds showed pharmacokinetic properties suitable for topical formulation, thus suggesting that the novel rhodanine derivatives could represent effective agents to be used as dual anti HIV/HSV microbicides in PrEP approaches.

Effect of fennel vaginal cream on sexual function in postmenopausal women: A double blind randomized controlled trial.

Objective: The aim of this study was to assess the effect of fennel on sexual function in postmenopausal women. It was a randomized controlled trial in 60 postmenopausal women with sexual dysfunction who were randomly assigned to two groups receiving either fennel vaginal cream (n=30) or placebo (n=30). Vaginal atrophy in the women was assessed using symptoms such as pallor, dryness, dyspareunia, itching and burning. The pH of the vagina and cytology of the vaginal mucosa were also measured at baseline and 8 weeks after the intervention. All participants were requested to fill out the Female Sexual Function Index (FSFI) at baseline and after 8 weeks. The intervention group was requested to use fennel vaginal cream (5 grams) every night, while the control group used placebo each night for 8 weeks. The data were analyzed using the independent t-test and Chi-square, Mann-Whitney and Wilcoxon tests. All areas of sexual function including arousal, lubrication, orgasm, sexual satisfaction and pain improved in both fennel and placebo groups after 8 weeks; however, the differences in the fennel group were more evident (p<0.05). The total FSFI score was significantly higher in the fennel group compared to the control group (8.2 ±9.4 and 8.03±10.36 before the intervention and changing to 33.79±0.7 and 18.99±1.09 after the intervention in the fennel and placebo groups, respectively; p<0.001). Discussion: According to our results, fennel vaginal cream is an effective means of improving sexual activity in postmenopausal women. The use of this product in women who have sexual dysfunction and contraindications for hormone therapy is recommended.

The effect of prebiotic vaginal gel with adjuvant oral metronidazole tablets on treatment and recurrence of bacterial vaginosis: a triple-blind randomized controlled study.

PURPOSE: Bacterial vaginosis is a change in the normal vaginal bacterial flora that leads to loss of hydrogen peroxide producing lactobacilli and overgrowth of predominantly anaerobic bacteria. The present study was conducted to compare the effects of prebiotic vaginal gel with oral metronidazole tablet and metronidazole tablet alone on treatment and recurrence of bacterial vaginosis. METHODS: The present triple-blind randomized clinical trial was conducted in Sadatmandi Hospital in Robat-Karim town, where 100 patients were randomly divided into intervention (receiving a 5 mg prebiotic vaginal gel applicator plus three 250 mg metronidazole tablets per day for 7 days) and control (receiving a 5 mg placebo vaginal gel applicator and three 250 mg metronidazole tablets per day for 7 days) groups. Then, patients were assessed for bacterial vaginosis on 90 ± 3 day after treatment. Data collected were analyzed in SPSS-21 using Chi square, repeated measures, and student's t tests at a significance level of P < 0.05. RESULTS: The results obtained showed no significant difference between the two groups in terms of personal and social characteristics, clinical complaints, or laboratory markers. On the 10th day, healing rate based on Amsel and Nugent criteria was 76% in the intervention group and 30% in the control group [odds ratio (OR) 4.3; 95% confidence interval (CI) 2.7-9.4]. On the 90th day, healing rate was 84% in the intervention group and 62% in the control group (OR 3.7; 95% CI 1.3-8.9). CONCLUSIONS: Adjuvant treatment with prebiotic vaginal gel improves the efficacy of bacterial vaginosis treatment.

An intravaginal ring that releases three antiviral agents and a contraceptive blocks SHIV-RT infection, reduces HSV-2 shedding, and suppresses hormonal cycling in rhesus macaques.

Women globally need access to multipurpose prevention technologies (MPTs) that prevent human immunodeficiency virus (HIV), sexually transmitted infections that increase HIV acquisition/transmission risk, and unintended pregnancy. Seeking an MPT with activity against HIV, herpes simplex virus-2 (HSV-2), and human papillomavirus (HPV), we developed a prototype intravaginal ring (IVR), the MZCL IVR, which released the antiviral agents MIV-150, zinc acetate, and carrageenan (MZC for short) and the contraceptive levonorgestrel (LNG). Previously, we showed that an MZC gel has potent activity against immunodeficiency viruses, HSV-2, and HPV and that the MZCL (MZC with LNG) IVR releases all four components in macaques in vivo at levels associated with efficacy. Vaginal fluid from treated macaques has in vitro activity against HIV, HSV-2, and HPV. Herein, we assessed the ability of the MZCL IVR to protect macaques against repeated co-challenge with HSV-2 and SHIV-RT (simian immunodeficiency virus [SIV] containing the reverse transcriptase gene from HIV) and prevent hormonal cycling. We evaluated in vivo drug release in co-challenged macaques by measuring drug levels in blood and vaginal fluid and residual drug levels in used IVRs. The MZCL IVR significantly prevented SHIV-RT infection, reduced HSV-2 vaginal shedding, and prevented cycling. No non-nucleoside HIV reverse transcriptase inhibitor (NNRTI)-resistant SHIV was detected in macaques that became infected after continuous exposure to MZC from the IVR. Macaques wearing the MZCL IVR also had carrageenan levels in vaginal fluid expected to protect from HPV (extrapolated from mice) and LNG levels in blood associated with contraceptive efficacy. The MZCL IVR is a promising MPT candidate that warrants further development.

Beneficial effects of a Coriolus versicolor-based vaginal gel on cervical epithelization, vaginal microbiota and vaginal health: a pilot study in asymptomatic women.

BACKGROUND: To assess the effect of a 12-day treatment using a vaginal gel based on niosomes containing hyaluronic acid, ß-glucan, alpha-glucan oligosaccharide, Coriolus versicolor, Asian centella, Azadirachta indica and Aloe vera on vaginal microbiota, cervical epithelization and vaginal health. METHODS: Open-label, prospective pilot study conducted in asymptomatic women in daily practice. Cervical epithelization was evaluated by colposcopy using an ectopy epithelization score (from 5: no ectopy to 1: severe ectopy and bleeding), vaginal microbiota using the VaginaStatus-Diagnostic test (Instiüt für Mikroökologie, Herborn, Germany) and further rated by the investigator using a 5-point Liker scale (from 5: normal to 1: very severe deterioration in which all evaluated species were altered), and vaginal health using the Vaginal Health Index. RESULTS: In 21 women, a positive effect to improve epithelization of the cervical mucosa, with a mean score of 4.42 at the final visit as compared to 3.09 at baseline (P < 0.0001) (43% improvement). In 10 women, there was a trend of improving of vaginal microbiota status, with a mean score of 4.0 at the final visit vs. 3.3 at baseline (P = NS) (21.2% improvement). In 11 women, the Vaginal Health Index increased from 19.0 at baseline to 22.3 at the final visit (P = 0.007). The concentration of Lactobacillus spp. increased 54.5% of women and pH decreased from 4.32 to 4.09. CONCLUSIONS: These encouraging preliminary results provide the basis for designing a randomized controlled study, and for potential use in human papilloma virus infection. TRIAL REGISTRATION: ISRCTN77955077 . Registration date: February 15, 2017. Retrospectively registered.

Vaginal Testosterone Cream vs Estradiol Vaginal Ring for Vaginal Dryness or Decreased Libido in Women Receiving Aromatase Inhibitors for Early-Stage Breast Cancer: A Randomized Clinical Trial.

IMPORTANCE: Aromatase inhibitors (AI) are associated with significant urogenital atrophy, affecting quality of life and drug compliance. OBJECTIVE: To evaluate safety of intravaginal testosterone cream (IVT) or an estradiol-releasing vaginal ring (7.5 µg/d) in patients with early-stage breast cancer (BC) receiving an AI. Intervention was considered unsafe if more than 25% of patients had persistent elevation in estradiol (E2), defined as E2 greater than 10 pg/mL (to convert to pmol/L, multiply by 3.671) and at least 10 pg/mL above baseline after treatment initiation on 2 consecutive tests at least 2 weeks apart. DESIGN, SETTING, AND PARTICIPANTS: Postmenopausal (PM) women with hormone receptor (HR)-positive stage I to III BC taking AIs with self-reported vaginal dryness, dyspareunia, or decreased libido were randomized to 12 weeks of IVT or an estradiol vaginal ring. Estradiol was measured at baseline and weeks 4 and 12 using a commercially available liquid chromatography and tandem mass spectrometry assay; follicle-stimulating hormone levels were measured at baseline and week 4. Gynecologic examinations and sexual quality-of-life questionnaires were completed at baseline and week 12. This randomized noncomparative design allowed safety evaluation of 2 interventions concurrently in the same population of patients, reducing the possibility of E2 assay variability over time and between the 2 interventions. MAIN OUTCOMES AND MEASURES: The primary objective of this trial was to evaluate safety of IVT or an estradiol vaginal ring in patients with early-stage BC receiving an AI; secondary objectives included evaluation of adverse events, changes in sexual quality of life using the Cancer Rehabilitation Evaluation System sexuality subscales, changes in vaginal atrophy using a validated 4-point scale, and comparison of E2 levels. RESULTS: Overall, 76 women signed consent (mean [range] age, 56 [37-78] years), 75 started treatment, and 69 completed 12 weeks of treatment. Mean (range) baseline E2 was 20 (<2 to 127) pg/mL. At baseline, E2 was above the postmenopausal range (>10 pg/mL) in 28 of 76 women (37%). Persistent E2 elevation was observed in none with a vaginal ring and in 4 of 34 women (12%) with IVT. Transient E2 elevation was seen in 4 of 35 (11%) with a vaginal ring and in 4 of 34 (12%) with IVT. Vaginal atrophy and sexual interest and dysfunction improved for all patients. CONCLUSIONS AND RELEVANCE: In PM women with early-stage BC receiving AIs, treatment with a vaginal ring or IVT over 12 weeks met the primary safety end point. Baseline elevation in E2 was common and complicates this assessment. Vaginal atrophy, sexual interest, and sexual dysfunction were improved. Further study is required to understand E2 variability in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00698035.

Formulation and evaluation of anise-based bioadhesive vaginal gels.

Various formulations of anise-based bioadhesive gels are prepared. Freeze-drying method was successfully employed and superporous scaffolds were obtained. The resulting porous microarchitectures are strongly influenced by the composition of hydrogel formulations and temperature of freezing. Anise-based hydrogels frozen in liquid nitrogen and lyophilized generate regular assembly of polyhedral pores. For Carbopol 934-based hydrogels it was determined G'>G'' for whole tested strain amplitude range indicating solid-like behaviour due to their dense network and entanglement and interaction through hydrogen bonds and van-der Waals forces. For sodium alginate-based hydrogels it was determined G''>G' for whole tested strain amplitude range accompanied by the extended linear viscoelastic region indicating liquid-like behaviour due to the formation of a stable "pseudo-gel" structure. Biocompatibility features of tested hydrogels were evaluated by contact angle measurements and determination of surface tension parameters. It was found that all anise-based hydrogel formulations manifest modest activity against S. aureus and S. lutea and no activity against tested Gram negative bacteria. Carbopol 934-based hydrogels containing anise exhibit antifungal activity against C. albicans, C. glabrata and C. Parapsilosis.

Efficacy, tolerability and safety of a new medical device, Monurelle Biogel(®) vaginal gel, in the treatment of vaginal dryness: a randomized clinical trial in women of reproductive age.

OBJECTIVE: To prove the efficacy, tolerability and safety of Monurelle Biogel(®) (ZP-025) vaginal gel, which contains a purified, dialyzed, lyophilized bovine colostrum, in women of reproductive age suffering from vaginal dryness. DESIGN: Randomized clinical trial (RCT) (Z7213M01). SETTING: Five University Gynaecological Units. PATIENTS: Ninety-five subjects were allocated at random to receive either ZP-025 (n=48) for about 23 intermenstrual days (1 or 2 times/daily intra-vaginally) or no treatment (lubricants on demand were allowed). MAIN OUTCOME MEASURES: Change of Verbal Rating Scale (VRS) total and single score for vaginal symptoms, Vaginal Health Index (VHI) score, Female Sexual Function index (FSFI) and Female Sexual Distress Scale-revised (FSDS-R) scores. RESULTS: A total number of 85 subjects was evaluable for primary analyses. Symptoms (VRS) of vaginal discomfort improved significantly already after 11 days, as compared to the control arm (p<0.0001). The mean VHI score was also significantly higher in ZP-025 group (p<0.001) at the end of the study. The analysis of covariance with the baseline value as covariate carried out on the FSFI Total Score showed a statistically significant difference in favour of the ZP-025 arm (p<0.032). A shift from presence to absence of sexual distress (≤11 points) was more prominent in the ZP-025 arm [10 subjects (40%) in the ZP-025 arm (p<0.0001) and 6 subjects (21.4%) in the control arm (p=0.01)]. Women reported a compliance rate of 100% for one ZP-025 application/day. Local tolerability of ZP-025 was excellent or good in 82.9% of the subjects. CONCLUSIONS: The present multicentre RCT supports the use of Monurelle Biogel(®) in women of reproductive age reporting symptoms of vaginal dryness. A positive impact on vaginal health and sexual function was also evident.

A Phase 1 Trial to Assess the Safety, Acceptability, Pharmacokinetics, and Pharmacodynamics of a Novel Dapivirine Vaginal Film.

BACKGROUND: Films may deliver antiretroviral drugs efficiently to mucosal tissues. In this first in-human trial of a vaginal film for delivering the nonnucleoside reverse transcriptase inhibitor dapivirine, safety, pharmacokinetics, and pharmacodynamics of film and gel formulations were compared with placebo. METHODS: Sixty-one healthy HIV-negative women were randomized to daily dapivirine (0.05%) or placebo gel, or dapivirine (1.25 mg) or placebo film for seven days. The proportion of participants experiencing grade 2 and higher adverse events related to study product were compared. Plasma dapivirine concentrations were quantified. Paired cervical and vaginal tissue biopsies obtained ∼2 hours after the last dose were measured for tissue drug concentration and exposed to HIV in an ex vivo challenge assay. RESULTS: Two grade 2 related adverse events occurred in the placebo film group. Women randomized to gel and film products had 4 log10 higher of dapivirine in cervical and vaginal tissues than plasma. Although gel and film users had comparable plasma dapivirine concentrations, tissue concentrations of dapivirine were 3-5 times higher in the gel users when compared with film users. HIV replication in the ex vivo challenge assay was significantly reduced in vaginal tissues from women randomized to dapivirine film or gel; furthermore, tissue drug concentrations were highly correlated with HIV protection. Women rated the film more comfortable with less leakage but found it more difficult to insert than gel. DISCUSSION: Both film and gel delivered dapivirine at concentrations sufficient to block HIV ex vivo. This proof-of-concept study suggests film formulations for microbicides merit further investigation.

Evaluation of antifertility effect of gel formulation containing sperm immobilizing factor: In vitro and in vivo studies.

Sexually active women often seek protection against unplanned pregnancies. Latter can be effectively controlled by consistent use of spermicides during each coital act. However, side effects associated with the use of available synthetic spermicidal agents have directed the interest towards identifying newer and safer agents. Present studies were undertaken to formulate a vaginal contraceptive gel, containing sperm immobilizing factor (SIF) isolated from Staphylococcus aureus using 1% w/v Carbopol. SIF loaded gel formulation was characterized for various in vitro parameters i.e. pH, spreadability, texture profiling, rheological properties, and in vitro release studies. The prepared formulation was found to possess significant spreading properties, gel firmness and strength, and released about 80% of SIF within 30min. Latter can completely immobilize human spermatozoa within 20s, at a dose of 200µg/ml. SIF in the proposed gel formulation showed 100% contraceptive effect when used at amount as low as of 10µg, thus confirming the possibility to develop it as a potent vaginal contraceptive for future use.