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Films have undoubtedly seen the most significant advances in their development in recent years of all the pharmaceutical forms for the vaginal administration of drugs. Films combine the advantages of gels and solid pharmaceutical forms, and their great versatility is largely determined by the numerous polymers that can be used for their fabrication. They may be based on many natural polymers, and cellulose derivatives, polyvinyl alcohol or acrylic derivatives – among others – are also frequently used. The combination of different polymers and the inclusion of plasticizing agents makes them extremely versatility for responding to a range of therapeutic needs. The techniques used to produce films have also undergone substantial development. Although the solvent casting technique is by far the most widely used in fabrication, alternative options have also emerged such as electrospinning, moulding extrusion and 3D printing. Various research groups have proposed a proliferation of assays to characterise vaginal films in recent years, which highlight the importance of the preliminary evaluation and determination of the films' uniformity, in addition to tests to determine their permeability and hydrophilic/hydrophobic coefficient and their mechanical properties, the application of imaging techniques and thermal analysis, and especially the evaluation of the mucoadhesive properties and control over the drug release. This article offers a critical overview of the advances in the development and fabrication of films intended for vaginal drug delivery, and summarises current clinical applications for vaginal films.

OBJECTIVE To determine the factors associated with delayed onset of active labor following labor induction with vaginal misoprostol. METHODS We conducted a prospective cohort study over 6 months at a tertiary hospital in Uganda. We enrolled mothers with pregnancies of at least 28 weeks, who were undergoing labor induction with 50 µg of vaginal misoprostol, administered every 6 hours with a maximum of four doses, and followed them up until onset of active labor. Labor onset was considered delayed if it occurred later than 12 hours after the first dose. Bivariate and multivariate analysis was performed to determine factors associated with delayed onset of active labor. RESULTS Of the 88 mothers enrolled, 22.7% (n=20) had delayed onset of active labor. Nulliparity (adjusted relative risk [aRR] 2.34, 95% confidence interval [CI] 1.17-4.68) and gestational age less than 37 weeks (aRR 3.79, 95% CI 1.40-10.23) were associated with delayed onset of active labor following vaginal misoprostol administration whereas higher body mass index (aRR 0.38, 95% CI 0.18-0.79) decreased the risk. CONCLUSION Delayed onset of active labor following labor induction remains an important obstetric care challenge. Mothers undergoing labor induction should have their body mass index documented, and nulliparous women and mothers at less than 37 weeks of gestation should have their labor monitored for a longer duration following labor induction.

Introduction: Atrophic vaginitis is a common problem in postmenopausal women and results from decreased levels of blood estrogen. It is associated with symptoms of itching, burning, dyspareunia, and postmenopausal bleeding. The present study evaluated the effects of fenugreek extract on atrophic vaginitis. Materials and Methods: This randomized controlled clinical trial was performed on 60 postmenopausal women in Ardabil, Iran, in 2018. The participants were selected using block randomization with the allocation ratio 1:1. Those in the intervention group received 0.5g (the applicator filled to the half-full mark) fenugreek vaginal cream 5% twice a week for 12 weeks. The control group received conjugated estrogens vaginal cream at the dose of 0.625 mg (the applicator filled to the half-full mark) containing 0.3 mg of conjugated estrogens. Atrophic vaginitis was evaluated before and after the treatment through clinical examination, clinical signs, and measurement of Vaginal Maturation Index (VMI). Findings: After the 12-week intervention and modification of the baseline score, the mean (standard error) score for atrophic vaginitis signs was 3.100 (1.43-4.75). This difference was statistically significant in intragroup comparison and in favor of the control group in intergroup comparison (p=0.001). VMI was less than 49% in 86.7% and 46.7% of the participants in the intervention and control groups, respectively. This was a significant difference in favor of the control group (p=0.001). Conclusion: The results of this study showed that total fenugreek extract could be effective in treating signs of atrophic vaginitis, but it was not as effective as ultra-low-dose estrogen.

To compare the effectiveness of misoprostol and dinoprostone tablets administered vaginally 3 hours before copper intrauterine device (IUD) insertion vs placebo in reducing pain and increasing ease of insertion among nulliparous women.Randomized controlled trial.Tertiary referral hospital.A total of 129 nulliparous women requesting a Copper T380A IUD insertion.Women were randomized to receive 200 μg misoprostol or 3 mg dinoprostone or placebo 3 hours before IUD insertion.Primary outcome was patient-reported pain during IUD insertion using a 10-cm visual analog scale (VAS). Secondary outcomes include provider ease of insertion, women satisfaction level, and side effects.Participants' baseline characteristics were comparable between the study groups. Mean pain score during IUD insertion was lower with misoprostol than placebo (3.1 ± 2.3 vs 4.4 ± 2.2; P = .02) and dinoprostone compared to placebo (2.4 ± 1.8 vs 4.4 ± 2.2; P .001). Clinicians reported easier IUD insertion with misoprostol than placebo (2.4 ± 1.7 vs 4.0 ± 2.4; P = .001) and dinoprostone compared to placebo (2.0 ± 1.5 vs 4.0 ± 2.4; P .001). Women's satisfaction levels were higher with both misoprostol and dinoprostone than placebo (P .001). Side effects did not differ among the 3 study groups.Premedication with vaginal misoprostol or dinoprostone effectively lowered pain during copper IUD insertion. However, the reduction in pain scores was clinically significant only in women who received dinoprostone. In both the misoprostol and dinoprostone groups, clinicians found the procedure easier, and women were more satisfied with IUD insertion. Side effects and complications were similar in all groups.

Background A newly developed multiple use applicator for vaginal tablets/vaginal inserts* was evaluated for its general suitability. There are no standard procedures described in guidelines or general accepted publications as to how this kind of product should be tested for suitability of purpose. Methods Due to the lack of existing standard procedures, three separate tests were designed and successful executed: (a) First, a patient acceptability evaluation was carried out as part of a phase III trial (registered in EudraCT on 9 Jan 2017, number 2017-000142-22 2. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number%3A2017-000142-22). (b) Secondly, a cleaning procedure for the applicator after simulated multiple use was developed and verified in order to prove a minimized risk of microbiological contamination of the device. A newly developed vaginal fluid to simulate multiple applications was applied for this trial. (c) Lastly, a third trial evaluated the mechanical stability and proper functionality of the applicator after multiple simulated uses. Even potential abrasion of material of the device was checked. Results Acceptable patient compliance of the new multiple use applicator was verified after 2 weeks of daily use. Furthermore, diary data assessments of patients participating in the Pharmacodynamic part of the trial were evaluated as well. Overall, patient acceptability of the new applicator was proven. The easy-to-use cleaning procedure for the applicator, which can even be carried out in a domestic environment, was developed and successfully verified for effectiveness, meeting all microbiological acceptance criteria for vaginal products of the European Pharmacopeia. The mechanical stability and proper functionality of the applicator after 50 simulated uses was also evaluated. All tested applicator batches (fresh and aged) passed the final evaluation, with no limitations in functionality. Conclusion The tests developed and executed consider various compliance aspects of the newly developed applicator. Results of these individual tests met the expectations and/or the predefined acceptance criteria. All included trials performed produced results justifying and qualifying the applicator for the intended multiple-use. The procedures outlined may also be a guide as to how this kind of medical device can be tested for suitability. Trial registration Registered in EudraCT, number 2017-000142-22, start date 24 May 2017.

Objective(s) To assess efficacy and safety of self-administered 3 mg dinoprostone vaginally in reducing pain during copper intrauterine device (IUD) insertion in parous women. Design Randomized, double-blinded, placebo-controlled trial. Setting Family planning clinic in a tertiary referral hospital. Patient(s) Multiparous women who were attending a family planning clinic and requesting copper IUD insertion. Interventions(s) We randomly assigned 160 participants into two groups: The dinoprostone group (n = 80) received 3 mg dinoprostone vaginally, and the placebo group (n = 80) received placebo vaginally. Main Outcome Measure(s) Our primary outcome was mean pain scores during IUD insertion. Our secondary outcomes were mean pain scores during tenaculum application, during uterine sounding, and 15 minutes after insertion, ease of insertion, satisfaction score, need for additional analgesics, and side-effects. Result(s) Both groups showed no significant difference in anticipated pain score (P=.41), pain during tenaculum placement (P=.22), and pain during sound insertion (P=.07). The dinoprostone group had significantly lower pain scores during IUD insertion (34.8 ± 10.1 vs. 57.8 ± 11.8) and 15 minutes after insertion (20.6 ± 6.4 vs. 29.6 ± 6.2), easier IUD insertion (43.6 ± 21.9 vs. 64.7 ± 18.1), and higher satisfaction (83.9 ± 11.6 vs. 63.0 ± 9.1) compared with the placebo group. Fewer patients required additional analgesics in the dinoprostone group compared with the placebo group (P=.01). Side-effects were similar between the groups. Conclusion(s) Self-administered 3 mg dinoprostone vaginally before copper IUD insertion in parous women reduces pain scores during IUD insertion, making insertion easier and increasing women’s satisfaction, with tolerable side-effects. Clinical Trial Registration Number NCT04046302

Vaginal drug delivery systems are often preferred for treating a variety of diseases and conditions of the female reproductive tract (FRT), as delivery can be more targeted with less systemic side effects. However, there are many anatomical and biological barriers to effective treatment via the vaginal route. Further, biocompatibility with the local tissue and microbial microenvironment is desired. A variety of in vitro and ex vivo models are described herein for evaluating the physicochemical properties and toxicity profile of vaginal drug delivery systems. Deciding whether to utilize organoids in vitro or fresh human cervicovaginal mucus ex vivo requires careful consideration of the intended use and the formulation characteristics. Optimally, in vitro and ex vivo experimentation will inform or predict in vivo performance, and examples are given that describe utilization of a range of methods from in vitro to in vivo. Lastly, we highlight more advanced model systems for other mucosa as inspiration for the future in model development for the FRT.

To determine the proportion of complete abortion without surgical intervention for patients who chose medication abortion with vaginal compared to buccal misoprostol following oral mifepristone through 70 days of gestation.We performed a retrospective cohort study. We reviewed charts via electronic medical record data abstraction of patients receiving medication abortion with mifepristone and buccal or vaginal misoprostol between September 1, 2017 and August 1, 2019. Primary outcome was complete abortion without surgical intervention for any indication. Secondary outcomes were ongoing pregnancy and uterine aspiration for indications other than ongoing pregnancy.There were 14,504 encounters included in the data set. Of the 4814 patients who took vaginal misoprostol and the 4011 patients who took buccal misoprostol for whom follow up data is available, 4640 (96.4%) and 3917 (97.7%) had a complete abortion without surgical intervention, respectively (p = 0.002). At64 days of gestation, complete abortion was 96.6% for vaginal administration compared to 98.0% for buccal (p = 0.001). At 64 to 70 days of gestation, complete abortion was 92.7% for vaginal administration compared to 93.2% for buccal (p = 0.08). Of the 1128 patients who took vaginal misoprostol at less than 6 hours after mifepristone, 95.3% experienced a complete abortion.Buccal administration of misoprostol is associated with a higher proportion of complete abortion before 64 days of gestation compared to vaginal misoprostol. Clinically, vaginal misoprostol is an effective route of administration through 70 days of gestation.Medication abortion with vaginal misoprostol is effective when administered through 70 days of gestation and with shorter intervals between mifepristone and misoprostol. Prospective research to better estimate effectiveness is warranted. Expanding medication abortion options promotes patient autonomy amid increasing restrictions and bans on abortion.

Induction of labour is one of the most common antepartum intervention. There are numerous methods available but the most commonly used in Malaysian public hospital is the intravaginal dinoprostone. This survey highlighted the various practices of using dinoprostone for different group of pregnant women which are unfortunately, not supported by robust clinical evidence. As such, it calls for futher studies to allow future practice standardization. Alternatively, the use of misoprostol for induction of labour, which has better data profile, should also be considered.

The current study aimed at assessing the overall efficacy of probiotics for the treatment of bacterial vaginosis (BV) through the review of relevant studies.A systematic literature review was conducted based largely on the following electronic databases updated to May 2021: Embase, the Cochrane Library, and PubMed, with the use of keywords. The investigators also thoroughly reviewed key pertinent sources in the literature for further inclusion.Eighteen studies including 1651 patients were selected in the present meta-analysis. In comparison with antibiotics, antibiotics plus probiotics significantly decreased the recurrence rate of BV (at 1-3 months and overall analysis) and increased the cure/remission rate of BV (at 1-3 months and overall analysis). Compared with placebo, probiotics decreased the recurrence rate of BV (at 1-3 months and overall analysis) and increased the cure/remission rate of BV (at 1-3 months). Compared with antibiotics, probiotics significantly decreased the recurrence rate of BV (at1 month, 1-3 months and overall analysis) as well as the incidence of adverse events (AEs) (at less than 1 month) and increased the cure/remission rate of BV (at 1-3 months).In comparison with short-term probiotics treatment (1 month), long-term probiotics treatment (1-3 months) yields superior beneficial outcomes and efficacy in the treatment of BV.

Comparison of dinoprostone, misoprostol and amniotomy in labor induction.The study group included a total of 437 women who underwent consecutive induction of labor after evaluation of the indication and Bishops score. The most common indications were: postmaturity, hypertensive disease, diabetes mellitus and fetal growth restriction. In 327 cases we chose to induce labor using vaginal tablets of dinoprostone at a dose of 0.75mg, in 36 cases dinoprostone at a dose of 3mg, in 16 cases we used a vaginal insert of misoprostol (200 µg), and in 58 cases amniotomy was performed.In the subgroup of dinoprostone (0.75mg) the rate of vaginal delivery (including extraction delivery) was 90.2%, in the subgroup of dinoprostone (3mg) it was 91.6%, in the subgroup of misoprostol it was 100% and in the subgroup of amniotomy it was 93.1%. The time period between onset of labor induction and delivery was an average of 15.75 hours in the dinoprostone (0.75mg) subgroup, 21.41 hours in the dinoprostone (3mg) subgroup, 17.41 hours in the misoprostol subgroup and 7.49 hours in the amniotomy subgroup.Subgroup of patients with misoprostol showed the highest rate of vaginal delivery after labor induction. In the subgroup with amniotomy, the shortest time period between onset of induction and delivery was reached.

From 2016 to 2018, a total of 300 pregnant women underwent induction of labour. Those women were allocated in two groups according to the initial dose of misoprostol. Group I (150 women) received intravaginally 50 µg misoprostol followed by 25 µg every four hours, up to a maximum of four doses whereas in group II (150 women) the initial dose was 25 μg intravaginal followed by the same dose every four hours up to a maximum of four doses. Women with previous uterine scar, abnormal foetal heart rate, severe foetal malformation, foetal growth restriction or multiple pregnancy were excluded. The aim of study was to compare the effectiveness (hours until delivery) and perinatal outcomes of both schemes of cervical ripening. Initial doses of 50 μg of misoprostol reduced the time until delivery (17.65 ± 8.2 hours vs. 20.85 ± 9.3 hours

To evaluate the cost-effectiveness of a strategy based on direct-acting uterine curettage (UC) versus a pre-direct-acting misoprostol (1600 mg) in patients with missed abortion (MA), from the perspective of a National Health System.An open prospective cohort study was carried out at Reina Sofía University Hospital (Córdoba, Spain) from January 1, 2019 to December 31, 2019 in 180 patients diagnosed with MA. The patients chose medical treatment with intravaginal misoprostol (800 μg/4 h) or UC after receiving complete and detailed information. The effectiveness, clinical characteristics of the patients, costs of treating and managing the disease, and satisfaction with the procedures were recorded.One hundred and forty-five patients (80.6%) chose misoprostol versus 35 patients (19.4%) who chose UC. The effectiveness of misoprostol has been 42% evaluated at 48 h; UC success rate has been 100%. The incidence of side effects is significantly higher in patients treated with misoprostol (p 0.05); as well as the number of care received by the patient (p 0.05). Satisfaction is higher in patients treated with UC (p 0.05). However, the cost is almost 5-folds higher in patients treated with UC (p 0.05).UC has a higher success rate, greater satisfaction, and a lower incidence of side effects, although significantly increases the cost compared to misoprostol in MA.

This prospective, open-label, multicentre, multinational, randomised trial investigated the non-inferiority of treatment with a vaginal hormone-free moisturising cream compared to a vaginal estriol (0.1%) cream in a panel of post-menopausal women suffering from symptoms of vulvovaginal dryness in a parallel group design. In total, 172 post-menopausal women were randomly allocated to either one of the two treatments, each administered for 43 days. The primary endpoint was the total severity score of subjective symptoms (dryness, itching, burning and pain unrelated to sexual intercourse) of the respective treatment period. Secondary endpoints were severity of single subjective symptoms (including dyspareunia if sexually active), impairment of daily life, Vaginal Health Index, as well as assessment of safety. In both groups, women treated with hormone-free moisturising cream and those treated with estriol cream, total severity score improved significantly compared to baseline by 5.0 (from 6.1 to 1.1) and by 5.4 (from 6.0 to 0.6), respectively, after 43 days of treatment (p < 0.0001). One-sided test of baseline differences (for a clinically relevant difference Δ = 1.5) confirmed the hormone-free moisturising cream to be non-inferior to the estriol cream. Severity of dyspareunia as well as impairment of daily life due to subjective symptoms, significantly improved for both treatment groups (p

HIV pre-exposure prophylaxis (PrEP) is dominated by clinical therapeutic antiretroviral (ARV) drugs. Griffithsin (GRFT) is a non-ARV lectin with potent anti-HIV activity. GRFT’s preclinical safety, lack of systemic absorption after vaginal administration in animal studies, and lack of cross-resistance with existing ARV drugs prompted its development for topical HIV PrEP. We investigated safety, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of PC-6500 (0.1% GRFT in a carrageenan (CG) gel) in healthy women after vaginal administration. This randomized, placebo-controlled, parallel group, double-blind first-in-human phase 1 study enrolled healthy, HIV-negative, non-pregnant women aged 24–45 years. In the open label period, all participants (n = 7) received single dose of PC-6500. In the randomized period, participants (n = 13) were instructed to self-administer 14 doses of PC-6500 or its matching CG placebo (PC-535) once daily for 14 days. The primary outcomes were safety and PK after single dose, and then after 14 days of dosing. Exploratory outcomes were GRFT concentrations in cervicovaginal fluids, PD, inflammatory mediators and gene expression in ectocervical biopsies. This trial is registered with ClinicalTrials.gov, number NCT02875119. No significant adverse events were recorded in clinical or laboratory results or histopathological evaluations in cervicovaginal mucosa, and no anti-drug (GRFT) antibodies were detected in serum. No cervicovaginal proinflammatory responses and no changes in the ectocervical transcriptome were evident. Decreased levels of proinflammatory chemokines (CXCL8, CCL5 and CCL20) were observed. GRFT was not detected in plasma. GRFT and GRFT/CG in cervicovaginal lavage samples inhibited HIV and HPV, respectively, in vitro in a dose-dependent fashion. These data suggest GRFT formulated in a CG gel is a safe and promising on-demand multipurpose prevention technology product that warrants further investigation.

This study aimed to evaluate the progesterone (P4) release profile provided by four commercially available intravaginal P4 devices, as well as the effect of circulating P4 concentrations exclusively from these devices on the development of the dominant follicle (DF) in Nelore (Bos indicus) cows. Therefore, non-lactating multiparous Nelore cows were enrolled in an experimental design, over three replicates, starting on Day -9 with the insertion of a reused P4 device (2 g - original P4 load) for 7 d, followed by two treatments of cloprostenol sodium (PGF; 0.482 mg), 24 h apart, on Days -3 and -2. Just before device removal, on Day -2, a norgestomet ear implant was inserted and, 2 d later (Day 0), at the time of norgestomet withdrawal, cows were randomly assigned to receive one of the intravaginal devices: Primer (0.5 g); Prociclar (0.75 g); Sincrogest (1 g); or CIDR (1.9 g), and 2 mg of estradiol benzoate (EB) im. Blood samples were collected immediately before P4 device insertion, 12 h later and daily over 15 d (1 d after P4 device removal). Ultrasound examinations were performed on Days 0, 7, 8, 9, 10, 12, and 14 to evaluate ovarian dynamics. Results are presented as mean ± SEM and differences were considered when P ≤ 0.05. Overall, the devices resulted in distinct circulating P4 concentrations over 10 d, varying according to their initial P4 load and P4 impregnated surface area. Primer provided the lowest circulating P4 concentrations over time, whereas, CIDR had the greatest concentration. Sincrogest and Prociclar were similar, producing intermediary circulating P4. There was no effect of treatment on the DF diameter on any specific day, nor on follicular growth rate from Day 7-10. However, the Primer device resulted in a greater mean DF diameter over time. Additionally, greater circulating P4 concentrations, mainly during the first 3 d of device insertion, were associated with smaller DF diameters regardless of the treatment. In conclusion, results from this study provided a better understanding of the P4 profile of intravaginal P4 devices, as well as, their effect on DF development in Bos indicus cows. These data contribute to optimize the use of P4 devices in the reproductive management of beef cattle.

Vaginal dryness is common during and after menopause due to declining estrogen. It is one of the symptoms of vulvovaginal atrophy (VVA), which is part of the genitourinary syndrome of menopause. This can be distressing for women and cause pain, discomfort, and dyspareunia. Vaginal dryness affects over 50% of postmenopausal women but is under-reported and thus under-treated due to barriers to seeking help. Estrogen replacement can resolve symptoms, but may be contraindicated or not desired by all women. Over-the-counter vaginal moisturizers and lubricants can ease the symptoms of VVA. However, their chemical composition varies enormously and some are known to cause detrimental effects due to unphysiological pH, osmolality, and additives. The primary purpose of this review is to assess both their efficacy and safety. Women should be directed toward products that are as 'body-similar' as possible to vaginal secretions in terms of pH and osmolality. Products with potentially harmful ingredients should be avoided. Lubricants can be trialed for sexual activity and moisturizers for symptom control, even if topical or systemic menopause hormone therapy is being used.

Introduction: We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration. Methods: This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reaction-time test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration. Results: Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented. Conclusion: Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.

Introduction Vulvar and vaginal atrophy (VVA) affects up to two thirds of postmenopausal women, with symptoms of vaginal dryness, dyspareunia, and vulvar/vaginal irritation. Despite the availability of various treatments, women express dissatisfaction with their options. An estradiol (E2; 4-µg and 10-µg) softgel vaginal insert was approved by the Food and Drug Administration (FDA) to treat moderate to severe dyspareunia, a symptom of VVA, due to menopause. These inserts were designed to treat VVA effectively and safely while avoiding some of the drawbacks of other administration methods. Areas covered This article reviews the physical characteristics and pharmacokinetic data of the E2 softgel vaginal insert. Primary and secondary efficacy endpoints and safety data are reviewed from the pivotal REJOICE trial (NCT02253173), and substudies that explore response rates, changes in vaginal epithelium by visual assessment, efficacy in patient subgroups, effects on sexual function, and patient satisfaction compared with other treatments. Expert opinion The E2 insert shows that vaginal drug delivery is an optimal route of administration for locally treating VVA. This E2 softgel vaginal insert is a safe and effective treatment for symptoms of postmenopausal VVA. The E2 insert's pharmacokinetic characteristics are related to its unique formulation, rapid dissolution, and minimal systemic absorption. Abbreviations AE: adverse event; AUC: area under the concentration-time curve; BMI: body mass index; Cavg: average concentration; CI: confidence interval; Cmax: maximum concentration; Cmin: minimum concentration; E2: estradiol; FDA: Food and Drug Administration; FSFI: Female Sexual Function Index; GSM: genitourinary symptoms of menopause: MBS: most bothersome symptom; NAMS: North American Menopause Society; OR: odds ratio; PI: pulsatility index; PK: pharmacokinetic; REVIVE: Real Women's Views of treatment options for menopausal Vaginal changEs; RI: resistance index; ROC: receiver operating characteristic; TEAE: treatment-emergent adverse event; tmax: time to maximum concentration; VVA: vulvar and vaginal atrophy.

Maternal natural vaginal progesterone (nVP) administration has been shown to reduce the risk of preterm birth (PTB). The largest randomized trial of nVP for PTB (OPPTIMUM) noted a sonographic reduction in neonatal brain injury following nVP treatment. We investigated the neuroinflammatory protective effect of maternal nVP in a mouse model for maternal inflammation. Pregnant mice (n = 24) were randomized to nVP (1 mg/day) or vehicle from days 13–16 of gestation. At days 15 and 16, lipopolysaccharide (30 μg) or saline were administered. Mice were sacrificed 4 h following the last injection. Fetal brains and placentas were collected. Levels of NF-κB, nNOS, IL-6, and TNFα were determined by Western blot. Maternal lipopolysaccharide significantly increased fetal brain levels of IL-6 (0.33 ± 0.02 vs. 0.11 ± 0.01 u), TNFα (0.3 ± 0.02 vs. 0.10 ± 0.01 u), NF-κB (0.32 ± 0.01 vs. 0.17 ± 0.01 u), and nNOS (0.24 ± 0.04 vs. 0.08 ± 0.01 u), and reduced the total glutathione levels (0.014 ± 0.001 vs. 0.026 ± 0.001 pmol/μl; p

Small-for-gestational-age (SGA) pregnancy is a condition often leading to labor induction due to concerns about the possibility of an increased risk for fetal morbidity and mortality. In this retrospective cohort study, we try to evaluate the safety of oral misoprostol for labor induction in near-term and term pregnancies in SGA fetuses compared to dinoprostone as well as to planned primary cesarean section. Retrospective analysis of labor indution and primary cesarean section in SGA pregnancies 37 weeks and beyond in a tertiary care centre. In total, 284 consecutive patients with SGA fetuses were included. 80 recieved oral misoprostol, 85 dinoprostone as vaginal Gel and 119 were delivered by means of primary cesarean section. Primary endpoints were umbilical aterial pH and APGAR 5′. Secondary endpoints were APGAR 1′ and 10′, rates of relevant acidosis with a pH

Background The non-nucleoside reverse transcriptase inhibitor dapivirine has been evaluated as a topical microbicidal agent to prevent HIV-1 acquisition. Several clinical trials have evaluated the pharmacokinetics of dapivirine when administered as a 25-mg intravaginal ring. Recent studies have focused on the distribution of dapivirine into breast milk. Drug distribution during lactation and breastfeeding can have implications in terms of infant drug exposure. Thus, sensitive bioanalytical tools are required to characterize the pharmacokinetics of dapivirine in breast milk. Methods Whole breast milk was spiked with dapivirine and internal standard. Lipid content was disrupted via pre-treatment with n-hexane, and supernatants were subjected to solid phase extraction. Extracted materials were subjected to liquid chromatographic-tandem mass spectrometric (LC-MS/MS) analysis. Separation occurred using a Waters BEH C8, 50 × 2.1 mm UPLC column with a 1.7 µm particle size and dapivirine was detected on an API 5000 mass analyzer. Methods were validated in accordance with FDA Bioanalytical Method Validation recommendations. Results The analytical method was optimized for dapivirine extraction from breast milk. The analytical measuring range of the assay was 10–1000 pg/mL. Calibration curves were generated via weighted linear regression of standards. Intra- and inter-assay precision and accuracy studies demonstrated %CVs ≤ 14.6% and %DEVs ≤ ±12.7%. Stability and matrix effects studies were also conducted and deemed acceptable. The method was applied to a previously reported phase 1 clinical trial and demonstrated appropriate performance in the quantitation of dapivirine in breast milk samples from lactating women. Conclusions An ultrasensitive LC-MS/MS assay has been developed and validated for the quantitation of dapivirine in breast milk. The described method meets validation acceptance criteria and has been applied to a phase 1 clinical trial.

To assess safety and efficacy of self-administered vaginal dinoprostone 12 hours before a 52-mg levonorgestrel intrauterine device (LNG-IUD) insertion in adolescents and young nulliparous women.Randomized controlled trial.Tertiary referral hospital.Nulliparous adolescents and young women aged 18-22 years.Participants were randomly assigned into 2 groups; the dinoprostone group (n = 65) received dinoprostone 3 mg vaginally, and the placebo group (n = 65) received placebo tablets vaginally.Primary outcome was pain scores during LNG-IUD insertion measured using a visual analogue scale. Secondary outcomes were pain scores during speculum insertion, tenaculum placement, uterine sounding, and 20 minutes postprocedure, ease of insertion, Women's satisfaction score, need for additional analgesics, and side effects.The dinoprostone group had significantly lower pain scores during LNG-IUD insertion (2.83 ± 1.08 vs 3.95 ± 1.63), tenaculum placement (2.97 ± 1.41 vs 4.55 ± 1.53) and sounding of uterus (3.55 ± 1.71 vs 5.12 ± 1.37) compared with the placebo group (P .001). No significant differences were found between both groups regarding anticipated pain scores (P = .85), pain during speculum insertion and 20 minutes postinsertion and insertion duration (P = .53). Women's satisfaction, provider reported ease of insertion, and need for additional analgesia were significantly better among dinoprostone users (P .001,.001, and .02, respectively). Side effects and procedure complications were similar for the 2 groups.Self-administered dinoprostone 3 mg vaginally 12 hours before a 52-mg LNG-IUD insertion in nulliparous adolescent and young women effectively reduced pain during insertion and increased women's satisfaction and ease of insertion reported by clinicians.

We examined the effects of human chorionic gonadotropin (hCG) treatment on Day 5 (Day 0 = day of artificial insemination: AI) and intravaginal progesterone device (IVPD) treatment from Day 5 to 19 on the conception and detection rates of return to estrus (re-estrus) in lactating dairy cows. A total of 306 cows from a commercial dairy farm were divided into the following three groups on Day 5: non-treatment group (n = 128), untreated; hCG group (n = 71), 3,000 IU hCG was administered (intramuscularly); IVPD group (n = 107), IVPD was inserted into the vagina from Day 5 to 19. Re-estrus detection was performed up to Day 25. Pregnancy was diagnosed by rectal palpation between Day 50 and 60. There was an interaction between treatment and AI number (P < 0.01) on the conception rate of first-AI. For cows with more than three AIs, the IVPD treatment (66.7%) was more effective than the non-treatment (23.1%) (P < 0.05). The re-estrus detection rate was significantly (P < 0.05) higher in the IVPD group (60.7%) than that in the non-treatment group (41.4%) and tended (P < 0.1) to be higher than that in the hCG group (37.8%). Our results suggested that the conception rate can be improved by IVPD treatment, especially in cows with more than three AIs. In addition, IVPD treatment can induce higher estrus expression up to 25 days after AI in non-pregnant cows.

Research question Does subcutaneous progesterone provide similar live birth or ongoing pregnancy rates as vaginal progesterone in frozen embryo transfer (FET) cycles? Design Retrospective cohort study (n = 214 women), consisting of 107 women who received subcutaneous progesterone for FET in artificial cycles and 107 women receiving vaginal progesterone who were matched for age and treatment cycle rank acted as controls. All embryos were transferred in an artificial cycle with 6 mg per day oral oestradiol valerate starting on the second or third day of the menstrual cycle. Patients underwent transvaginal ultrasound on the 10th day of priming, and subcutaneous progesterone (50 mg/day) or vaginal progesterone (180 mg/day) was started if the endometrium had a trilinear pattern regardless of its thickness. Embryo transfer was carried out on the sixth day of progesterone administration. Oestradiol and progesterone were continued until a negative pregnancy test, 10 days after the transfer, or until the completion of 10th gestational week. Main outcome measures were live birth or ongoing pregnancy rates. Results Baseline characteristics were similar between the groups. Positive pregnancy test rates (64.5% versus 58.9%; P = 0.40; RR 1.1; 95% CI 0.89 to 1.35), live birth or ongoing pregnancy rates (39.3% versus 35.5%; P = 0.57; RR 1.11; 95% CI 0.78 to 1.56) and miscarriage rates (29% versus 25.5%; P = 0.68; RR 1.08; 95% CI 0.76 to 1.55) were similar in the subcutaneous progesterone and vaginal progesterone groups, respectively. Conclusions Subcutaneous progesterone seems to be an effective alternative to vaginal progesterone in patients undergoing FET. Randomized controlled trials comparing it with different progesterone preparations, routes and protocols are needed to better define its role.

Introduction Vaginal ring delivery of antiretroviral drugs may provide protection against acquisition of HIV-1 when used as Pre-Exposure prophylaxis. As part of a randomized placebo-controlled safety trial of a tenofovir disoproxil fumarate (TDF) intravaginal ring (IVR), we assessed product acceptability through surveys of women after continuous ring use. Methods Sexually active, HIV-negative women were enrolled to investigate the safety and pharmacokinetics of 3 months of continuous TDF IVR use. The study was designed to include 40 US participants randomly assigned (3:1) to a TDF or placebo IVR. Twelve were randomized to TDF and 5 to the placebo group before the study was electively discontinued because of the development of vaginal ulcerations in 8 women in the TDF group. Acceptability data were gathered via self-administered, computer-based questionnaires. Results The average age of the 17 participants was 31 years (range, 18-42 years). Sixteen participants (94%) completed all questions at 2 study visits. When asked about ring likeability after 1 month of ring use, 12 (75%) of 16 reported overall liking the ring, including 6 (75%) of 8 who developed ulcerations. In addition, 10 (83%) of 12 who had their menses during the first month of ring use were not bothered by the ring, and 11 (69%) of 16 stated that the ring was not bothersome with use during sex. Conclusions Despite unanticipated ulcers, TDF and placebo IVRs were acceptable to some women, even when used with menses and during sex, which is promising for continued development of IVRs for HIV prevention.

AIM To evaluate the efficacy and safety of 25 μg of estradiol gel on postmenopausal vaginal tissue. METHODS This randomized double-blind controlled trial included postmenopausal women with vaginal atrophy who attended our menopause clinic during July 2017-January 2018. Women were randomly assigned to the estradiol gel group or control group (K-Y® Jelly). Treatment consisted of 2 mL of product applied intravaginally daily for 2 weeks, and two doses per week for the next 6 weeks. The most bothersome symptom (MBS), vaginal health index (VHI), vaginal pH, vaginal maturation index, vaginal maturation value (VMV), female sexual function index (FSFI), serum estradiol level and endometrial thickness were evaluated at baseline, 4 and 8 weeks. RESULTS Seventy-five of 80 women completed the trial. After 8 weeks of treatment, VMV, VHI, vaginal pH and FSFI improved significantly in the estradiol group, with no observed change in the control group. The MBS was decreased in both groups with no significant difference between groups. Serum estradiol level and endometrial thickness were not significantly different between groups at baseline or at week 8. CONCLUSION Estradiol vaginal gel demonstrated an ability to reverse vaginal atrophy with a high safety profile and low systemic absorption of estradiol.

Misoprostol is a prostaglandin analog commonly used to induce termination of pregnancy. Clandestine home terminations complicate forensic fetal autopsy when a history of misoprostol use is withheld and the gross and histologic findings are sparse, as is often the case. One hundred thirty-two placentas with no vaginal misoprostol use, low-dose misoprostol use, and high-dose misoprostol use were reviewed for the presence, volume, and locations of microcrystalline cellulose and crospovidone, common tablet fillers in misoprostol tablets. Microcrystalline cellulose and/or crospovidone was identified in 0 (0%) of 88 cases with no vaginal administration or low-dose vaginal administration and 29 (66%) of 44 placentas with high-dose vaginal administration. When identified, microcrystalline cellulose and/or crospovidone is most commonly present on the maternal surfaces of the extraplacental membranes. The presence of microcrystalline cellulose and/or crospovidone was associated with smaller placental weight (Mann-Whitney U, P = 0.019). These fillers have a reasonable sensitivity for high-dose vaginal tablet use and are very specific. Although they are not diagnostic for misoprostol administration, they provide a finding that may prompt additional investigation into the nature of the vaginal tablet administered and the circumstances surrounding birth.

PurposeTo identify predictors of complete miscarriage after expectant management or misoprostol treatment of non-viable early pregnancy in women with vaginal bleeding.MethodsThis was a planned secondary analysis of data from a published randomized controlled trial comparing expectant management with vaginal single dose of 800 µg misoprostol treatment of women with embryonic or anembryonic miscarriage. Predefined variables—serum-progesterone, serum-β-human chorionic gonadotropin, parity, previous vaginal deliveries, gestational age, clinical symptoms (bleeding and pain), mean diameter and shape of the gestational sac, crown-rump-length, type of miscarriage, and presence of blood flow in the intervillous space—were tested as predictors of treatment success (no gestational sac in the uterine cavity and maximum anterior–posterior intracavitary diameter was ≤ 15 mm as measured with transvaginal ultrasound on a sagittal view) in univariable and multivariable logistic regression.ResultsVariables from 174 women (83 expectant management versus 91 misoprostol) were analyzed for prediction of complete miscarriage at ≤ 17 days. In patients managed expectantly, the rate of complete miscarriage was 62.7% (32/51) in embryonic miscarriages versus 37.5% (12/32) in anembryonic miscarriages (P = 0.02). In multivariable logistic regression, the likelihood of success increased with increasing gestational age, increasing crown-rump-length and decreasing gestational sac diameter. Misoprostol treatment was successful in 80.0% (73/91). No variable predicted success of misoprostol treatment.ConclusionsComplete miscarriage after expectant management is significantly more likely in embryonic miscarriage than in anembryonic miscarriage. Gestational age, crown-rump-length, and gestational sac diameter are independent predictors of success of expectant management. Predictors of treatment success may help counselling women with early miscarriage.