Combination of Soy Isoflavones, 8-Prenylnaringenin and Melatonin Improves Hot Flashes and Health-Related Quality of Life Outcomes in Postmenopausal Women: Flavie Study.

OBJECTIVES: This study aims to investigate the effects of a combination of soy isoflavones, 8-prenylnaringenin (8-PN), and melatonin in postmenopausal women suffering from moderate-to-severe hot flashes (HFs). METHODS: A multicenter, prospective, open-label study enrolled 44 postmenopausal women suffering from moderate-to-severe HFs (≥ 5 daily or ≥ 35 weekly) to receive 54.4 mg standardized soy isoflavones (including 24.5 mg genistein and 16.3 mg daidzein), 100 µg 8-PN, and 1 mg melatonin once daily for 12 weeks. The primary clinical outcomes included changes in health-related quality of life (HRQoL) scores (Menopause-Specific QoL questionnaire [MENQoL] and Cervantes Scale) and HFs following 4 and 12 weeks of treatment. Other analyses included treatment adherence, acceptability, tolerability, and safety. RESULTS: All of the four domains of MENQoL questionnaire significantly improved at 4 weeks (P < 0.05) and 12 weeks (P < 0.001), affecting significantly the vasomotor, psychosocial, and physical spheres (41.2%, 26.3%, and 25.0%; 12 weeks improvements, respectively). Similarly, in the menopause (39.3%) and psychic (51.7%) domains (both P < 0.05 at 12 weeks), the global score of the Cervantes Scale significantly increased at 4 weeks (18.6%) and 12 weeks (35.4%). Accordingly, moderate-to-severe HFs significantly decreased at 4 weeks compared to baseline (41.7% reduction) and further reduced at 12 weeks (76.5%), including the total number of episodes. CONCLUSIONS: Food supplements containing soy isoflavones, 8-PN, and melatonin showed an early and progressive benefit for reducing clinically significant HFs and for improving HRQoL across all domains, favorably affecting postmenopausal women's overall well-being.

Early Effect of 0.005% Estriol Vaginal Gel on Symptoms and Signs of Vulvovaginal Atrophy.

OBJECTIVES: This study aims to assess the effect of ultralow dose 0.005% estriol vaginal gel in women with genitourinary syndrome of menopause (GSM). METHODS: In this prospective and multicenter single-arm study, efficacy was assessed by the evaluation of the epithelial maturation value (MV), vaginal pH, symptoms and signs of vulvovaginal atrophy. Tolerability, acceptability, and the effect on intimate relationships were also evaluated. RESULTS: We included 35 postmenopausal women with moderate-to-severe vaginal dryness. The most bothering symptom reported was vaginal dryness. The mean increase in the MV after 7 and 14 days of treatment were 22.1 (P < 0.001) and 39.9 (P < 0.001) points, with an increase in the superficial cells of 17.7 percentage points (pp) (95% confidence interval [CI], 7.9-27.4; P < 0.001) and 41.4 pp (95% CI, 28.2-54.6; P < 0.001) observed at the timepoints. Additionally, the pH decreased by 0.6 ± 0.7 (mean ± SD) at 7 days (P < 0.0001) and by 1.1± 0.8 at 14 days (P < 0.0001) from a baseline mean value of 6.3 ± 0.8. The severity of vaginal dryness (range, 0 [none] to 3 [severe]) was significantly reduced by a mean of 1.4 points (P < 0.0001) at 7 days and 2 points (P < 0.0001) at 14 days. CONCLUSIONS: Ultralow dose 0.005% estriol vaginal gel produced a rapid improvement of most relevant symptoms and signs of GSM. This clinically meaningful response was observed from the initial days of treatment, confirming a fast onset and a progressive action.

Bioavailability of Oniria®, a Melatonin Prolonged-Release Formulation, Versus Immediate-Release Melatonin in Healthy Volunteers.

BACKGROUND: Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro. OBJECTIVES: The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin. METHODS: We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3). RESULTS: Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance. CONCLUSION: Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.

Bioavailability study of Enoxaparin Sodium Chemi (80 mg/0.8 mL) and Clexane (80 mg/0.8 mL) subcutaneous injection in healthy adults.

OBJECTIVE: The present study compared the bioavailability of subcutaneous (s.c.) Chemi Enoxaparin with Clexane (80 mg/0.8 mL) under fasting conditions in healthy subjects. MATERIALS AND METHODS: This study was an open-label, randomized, single-dose, two-treatment period crossover study. We included healthy male and female subjects aged 18 - 55 years with a body mass index of 18 - 30 kg/m2. The primary pharmacodynamic endpoints were anti-FIIa and anti-FXa activity. Bioequivalence was achieved when the 95% confidence interval (CI) for the geometric means of Cmax and AUC0-t was between 80.00 and 125.00%. RESULTS: 47 subjects were randomized for the treatment sequences. The 95% CI of the ratios of the geometric least squared means of anti-FXa activity was 96.28 - 102.65 IU/mL for Cmax and 100.67 - 105.15 h×IU/mL for the AUC0-t of Chemi Enoxaparin compared with those of Clexane, and for anti-FIIa activity, they were 86.65 - 96.73 IU/mL for the Cmax and 87.72 - 97.25 h×IU/mL AUC0-t, which met the criterion for bioequivalence. The number of subjects reporting at least 1 treatment-emergent adverse event (TEAE) was low, mostly of mild severity, and similar for both compounds. CONCLUSION: Chemi enoxaparin is bioequivalent to the reference enoxaparin, and both compounds show similar tolerability and safety profiles.

A Phase II Prospective, Randomized, Double-Blind, Placebo-Controlled and Multicenter Clinical Trial to Assess the Safety of 0.005% Estriol Vaginal Gel in Hormone Receptor-Positive Postmenopausal Women with Early Stage Breast Cancer in Treatment with Aromatase Inhibitor in the Adjuvant Setting.

LESSONS LEARNED: The levels of circulating follicle-stimulating hormone, luteinizing hormone, estriol, estradiol, and estrone remained unchanged after a 12-week treatment with 0.005% estriol vaginal gel in postmenopausal women receiving nonsteroidal aromatase inhibitors for hormone receptor-positive early breast cancer. These results support the safety of 0.005% estriol vaginal gel for the treatment of bothering symptoms of vulvovaginal atrophy in breast cancer survivors. The results provide clinicians with confidence in the use of this product in women who do not experience symptom relief with nonhormonal remedies. BACKGROUND: Symptoms of vulvovaginal atrophy associated with treatment with nonsteroidal aromatase inhibitors (NSAIs) negatively impact patients' quality of life and may affect adherence to NSAIs. Vaginal estrogens effectively improve these symptoms, although their safe use in breast cancer survivors remains unclear. METHODS: Postmenopausal women with hormone receptor-positive early breast cancer receiving NSAI and moderate-to-severe vaginal dryness were randomized to 0.005% estriol vaginal gel or placebo for 12 weeks. Circulating estrogens, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), were analyzed at baseline and at weeks 1, 3, 8, and 12. The primary safety outcome was the variation in serum FSH from baseline to week 12. RESULTS: Sixty-one women (mean age, 59 years) enrolled in the study. Small oscillations were observed in FSH and LH, although they were always maintained within the postmenopausal range. No significant differences were found in the variation of FSH and LH between baseline and week 12 from the physiological variation observed before treatment. Women receiving 0.005% estriol vaginal gel had slightly increased estriol levels at weeks 1 and 3, with a subsequent reduction until normalizing at week 12; estradiol and estrone remained the below limit-of-quantitation in almost all samples. CONCLUSION: Ultralow-dose 0.005% estriol vaginal gel did not significantly influence estrogens, FSH, and LH levels in women with breast cancer receiving NSAI. A transient negligible absorption of estriol and a nonsignificant variation of FSH after 12 weeks were observed. These findings provide confidence for the safe use of 0.005% estriol vaginal gel in women with breast cancer with an indication for treatment with vaginal estrogens.

Efficacy and safety of ultra-low dose 0.005% estriol vaginal gel for the treatment of vulvovaginal atrophy in postmenopausal women with early breast cancer treated with nonsteroidal aromatase inhibitors: a phase II, randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and safety of ultra-low dose 0.005% estriol vaginal gel in women with breast cancer receiving nonsteroidal aromatase inhibitors (NSAIs) and experiencing treatment-related vulvovaginal symptoms and signs. METHODS: Women with hormone receptor-positive early breast cancer receiving NSAIs were randomized to either estriol vaginal gel or placebo for 12 weeks. Vaginal maturation, vaginal pH, and total and individual scores of symptoms and signs of vulvovaginal atrophy were assessed at baseline and at weeks 3 and 12; sexual functioning was also evaluated using the Female Sexual Functioning Index (FSFI) questionnaire, as well as circulating estrogens, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). RESULTS: Sixty-one women with a mean age of 59 years were included: 50 received 0.005% estriol vaginal gel and 11 received placebo. Active treatment significantly improved maturation value and pH, vaginal dryness and global scores of symptoms and signs. Active treatment also increased the total FSFI score and all the FSFI domains, with the exception of pain. Small oscillations were observed in FSH and LH, which remained within the postmenopausal range. Estriol levels increased initially and normalized by week 12, and estradiol and estrone remained mostly undetectable throughout the study. CONCLUSIONS: Ultra-low dose 0.005% estriol vaginal gel showed efficacy in improving the symptoms and signs of vulvovaginal atrophy. These results, together with minimal oscillations in hormonal levels throughout the treatment, support the use of ultra-low dose 0.005% estriol vaginal gel as a treatment option for vulvovaginal atrophy in women with breast cancer receiving NSAIs with an indication for treatment with vaginal estrogens. : Video Summary:http://links.lww.com/MENO/A531.

Video Summary:http://links.lww.com/MENO/A531.

The impact of genitourinary syndrome of menopause on well-being, functioning, and quality of life in postmenopausal women.

OBJECTIVE: Symptoms of genitourinary syndrome of menopause (GSM) are bothersome to middle-aged and older women, and affect their quality of life (QoL), sexuality, and daily activities. The objective of the study was to evaluate the impact of vaginal symptoms and GSM on the well-being, functioning, and QoL of postmenopausal women from Spain. METHODS: This study involved 423 postmenopausal women participating in the GENISSE study (a multicenter, cross-sectional, descriptive, observational study) who presented at least 1 vaginal symptom. All women completed the "day-to-day impact of vaginal aging" (DIVA) questionnaire. Analysis of total scores and subdomains of the questionnaire were performed in women diagnosed with GSM and those without the condition. RESULTS: In these women, the highest mean scores on the DIVA questionnaire were found in the sexual functioning domain long version (mean 1.8; SD 1.0), followed by the sexual functioning domain short version (mean 1.7; SD 1.1), self-perception and body image (mean 1.4; SD 1.1), activities of daily living (mean 0.7; SD 0.8), and emotional well-being (mean 0.7; SD 0.8) scales. A total of 299 women (70.7%) had vaginal symptoms with a diagnosis of GSM, whereas 124 (29.3%) had no GSM diagnosis. Scores on the DIVA questionnaire were significantly higher in women with a diagnosis of GSM than in those without this condition. CONCLUSIONS: Vaginal symptoms impact the well-being, functioning, and QoL of postmenopausal women, especially sexual function, self-perception, and body image. This impact is significantly higher in women with GSM. Identifying and treating patients affected by vaginal symptoms and GSM may be beneficial for improving their QoL.

A Multicenter, Prospective, Randomized Controlled Trial to Evaluate the Additional Benefit of a Multistrain Synbiotic (Prodefen®) in the Clinical Management of Acute Viral Diarrhea in Children.

This randomized, open-label study evaluated the additional benefits of the synbiotic Prodefen® in the clinical management of acute diarrhea of suspected viral origin in children between 6 months and 12 years of age. Study outcomes included the duration of diarrhea, the recovery from diarrhea, and the tolerability and acceptance of the treatment. The proportion of patients without diarrhea over the study period was greater in the synbiotic group than in the control group at all study time points, showing a statistically significant difference on the fifth day (95% vs 79%, p < 0.001). The duration of diarrhea (median and interquartile range) was reduced by 1 day in the synbiotic-treated patients (3 [2-5] vs 4 [3-5], p = 0.377). The tolerability of the treatment regimen, as evaluated by the parents, was significantly better in those receiving the synbiotic than in the control group. Overall, 96% of the parents of children receiving the synbiotic reported being satisfied to very satisfied with the treatment regimen. The results of this study indicate that the addition of the synbiotic Prodefen® is a well-tolerated and well-accepted approach that provides an additional benefit to the standard supportive therapy in the management of acute viral diarrhea in children.