Pharmacokinetics and pharmacodynamics of three dosages of oestriol after continuous vaginal ring administration for 21 days in healthy, postmenopausal women.
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ABSTRACT:
SUBMITTER: Oliveira Filho RV
PROVIDER: S-EPMC6379216 | biostudies-literature | 2019 Mar
REPOSITORIES: biostudies-literature
Publications
Pharmacokinetics and pharmacodynamics of three dosages of oestriol after continuous vaginal ring administration for 21 days in healthy, postmenopausal women.
Oliveira Filho Raimundo Vieira de RV Antunes Natalícia de Jesus NJ Ilha Jaime de Oliveira JO Moreno Ronilson Agnaldo RA Wedemeyer Ralph-Steven RS Warnke André A De Nucci Gilberto G
British journal of clinical pharmacology 20181225 3
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Project description:For women in the United States who remain sexually active beyond child-bearing years, susceptibility to HIV infection remains, yet condom use is low. We assessed acceptability of the dapivirine vaginal ring (ring) among 96 postmenopausal US women enrolled in a placebo-controlled multisite phase II trial of the ring, using questionnaires and in-depth interviews. Three quarters of women reported "perfect" adherence (ring never out) over the 3-month trial period. At study exit, the ring was found to be very easy to use by 72%, very comfortable to wear by 65%, and 4% reported it ever interfered with their daily activities. The most common worries among participants at preinitiation had decreased significantly at study exit (e.g., worries about inserting the ring declined from 46% to 6%, discomfort during daily activities from 53% to 3%, ring not staying in place from 48% to 14%, all p < 0.0001). Despite some couples feeling the ring during sex, the ring was perceived as more suitable than condoms for prevention because it was not burdensome to use, did not interfere with erection, and provided (for some) additional vaginal lubrication. The ring is a promising, highly acceptable HIV prevention method that is suitable to the lives of postmenopausal women and their male partners and can provide them with an additional prevention choice. Clinical Trials Registration: NCT02010593.
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Project description:BackgroundAs part of a program to develop a novel estradiol-releasing contraceptive vaginal ring (CVR), we evaluated the pharmacokinetic (PK) profile of CVRs releasing segesterone acetate (Nestorone® (NES)) combined with one of three different estradiol (E2) doses.Study designA prospective, double-blind, randomized, multi-centered study to evaluate a 90-day CVR releasing NES [200mcg/day] plus E2, either 10mcg/day, 20mcg/day, or 40mcg/day in healthy reproductive-age women with regular cycles. Participants provided blood samples twice weekly for NES and E2 levels during the first 60 days (ring 1) and the last 30 days (ring 2) of use. A subset underwent formal PK assessments at ring initiation, ring exchange (limited PK), and study completion.ResultsThe main study enrolled 197 women; 22 participated in the PK substudy. Baseline characteristics between the main and PK participants were comparable, with an average BMI of 25.8 kg/m2 (SD 4.3). In the PK substudy, all three rings showed similar NES PK: mean area under the curve (AUC(0-72)) 34,181 pg*day/mL; concentration maximum (Cmax) 918 pg/mL; time to maximum concentration (Tmax) 3.5 h. For E2, the Cmax occurred at 2 h, and was significantly higher with the 20 mcg/day ring (mean 390 pg/mL); 10 mcg/day, 189 pg/mL, p=.003; 40 mcg/day, 189 pg/mL, p<.001), and declined rapidly to≤50 pg/mL for all doses by 24 h. For all subjects, the median E2 levels remained under 35 pg/mL during treatment.ConclusionPK parameters of NES were not affected when paired with different doses of E2, but E2 levels from all three doses were lower than anticipated and no dose response was observed.ImplicationsWhile these novel estradiol-releasing combination contraceptive vaginal rings provided sustained release of contraceptive levels of Nestorone over 90 days, the E2 levels achieved were not consistent with bone protection, and a dose-response was not observed.
| S-EPMC5948142 | biostudies-literature
Project description:BackgroundCiprofol, a novel intravenous anesthetic, which has primarily been used for the induction and maintenance of general anesthesia in adults, is characterized by rapid onset, short duration of action, and quick and smooth recovery. However, the pharmacokinetic characteristics of continuous infusions and the correlation between the plasma concentration and the bispectral index (BIS) in elderly patients are still unknown.MethodIn this randomized, controlled study, thirty elderly patients (62-78 years old) undergoing elective gastrointestinal tumor resection were treated with propofol (N = 15) or ciprofol (N = 15) as sedatives during anesthesia. After induction, ciprofol/propofol was continuously infused intravenously until the end of the operation. Perioperative vital signs, injection pain, adverse events (AEs), BIS values, eyelid reflex disappearance times, and recovery times were recorded. The plasma concentrations of ciprofol and propofol were measured by liquid chromatography tandem mass spectrometry (LC‒MS/MS) and the pharmacokinetics were determined by noncompartmental analysis.ResultsBoth drugs caused a decrease in blood pressure and heart rate after induction. Eight cases (53. 3%) of hypotension and 3 cases (20%) of bradycardia occurred in the propofol group, while 8 cases (53. 3%) of hypotension and 5 cases (33. 3%) of bradycardia occurred in the ciprofol group. At intubation, the ciprofol group experienced fewer fluctuations in blood pressure than the propofol group. Ciprofol resulted in only one case (6.7%) of mild injection pain, less than that produced by propofol (10/15, 66.7%) (P < 0.05). Anesthesia induction was successfully completed with both drugs, and there were no significant differences in eyelash reflex disappearance or recovery time between the two groups. The plasma concentrations during maintenance were relatively stable in both groups (propofol 1.78 ± 0.67 μg/mL, ciprofol 0.71 ± 0.23 μg/mL), and a suitable depth of sedation was achieved with a BIS of 40-60. The pharmacokinetic (PK) parameters for ciprofol are listed as follows: Maximum Plasma Concentration (Cmax) 6.02 ± 2.13 μg/ml; Time to Maximum Concentration (Tmax) 0.18 ± 0.62 min; Apparent Volume of Distribution (Vz) 3.96 ± 0.84 L/kg; Total Clearance (CL) 0.83 ± 0.14 L/h/kg; Half-life (t½) 3.47 ± 1.85 h; Area Under the Curve (AUC) 5000 ± 900 L/h/kg; Terminal Elimination Rate Constant (λz) 0.23 ± 0.07 1/h. Similar to propofol, the plasma concentration of ciprofol was linearly correlated with the BIS.ConclusionCiprofol, a novel intravenous anesthetic, can be safely and effectively used in elderly patient continuous infusion with minimal injection pain. Plasma concentrations of ciprofol correlate well with BIS values, helping control sedation depth. For elderly patients undergoing gastrointestinal tumor surgery, an optimal maintenance dose of 0.8 mg/kg/h is recommended.Trial registrationThis clinical trial (registration No: ChiCTR2100047580, https://www.chictr.org.cn . The pre-registration date was June 20, 2021, and the review approval and official case solicitation began in December 2021; Retrospectively registered) was conducted in accordance with the World Medical Congress Declaration of Helsinki and Good Clinical Practice guidelines. All study subjects provided written informed consent.
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Project description:AimsTo describe the pharmacokinetics (PK) and concentration-related effects of dobutamine in critically ill neonates in the first days of life, using nonlinear mixed effects modelling.MethodsDosing, plasma concentration and haemodynamic monitoring data from a dose-escalation study were analysed with a simultaneous population PK and pharmacodynamic model. Neonates receiving continuous infusion of dobutamine 5-20 μg kg-1 min-1 were included. Left ventricular ejection fraction (LVEF) and cardiac output of right and left ventricle (RVO, LVO) were measured on echocardiography; heart rate (HR), mean arterial pressure (MAP), peripheral arterial oxygen saturation and cerebral regional oxygen saturation were recorded from patient monitors.ResultsTwenty-eight neonates with median (range) gestational age of 30.4 (22.7-41.0) weeks and birth weight (BW) of 1618 (465-4380) g were included. PK data were adequately described by 1-compartmental linear structural model. Dobutamine clearance (CL) was described by allometric scaling on BW with sigmoidal maturation function of postmenstrual age (PMA). The final population PK model parameter mean typical value (standard error) estimates, standardised to median BW of 1618 g, were 41.2 (44.5) L h-1 for CL and 5.29 (0.821) L for volume of distribution, which shared a common between subject variability of 29% (17.2%). The relationship between dobutamine concentration and RVO/LVEF was described by linear model, between concentration and LVO/HR/MAP/cerebral fractional tissue oxygen extraction by sigmoidal Emax model.ConclusionIn the postnatal transitional period, PK of dobutamine was described by a 1-compartmental linear model, CL related to BW and PMA. A concentration-response relationship with haemodynamic variables has been established.
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Project description:BackgroundA relationship between the vaginal microbiota and tenofovir (TFV) concentrations and activity after topical administration has been previously reported.ObjectiveCONRAD A15-138 was a randomized, placebo-controlled Phase I study aimed at characterizing the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TFV and levonorgestrel (LNG) administered through a vaginal ring (IVR) for 90 days. Herein, we describe changes from baseline in the vaginal microbiota with IVR use and the impact of the vaginal microbiota on mucosal TFV PK.MethodsThe study screened 68 participants and randomized 47 (37 TFV/LNG, 10 placebo), assessing the vaginal microbiota by sequencing the V3-V4 regions of 16S rRNA genes prior to IVR insertion and monthly for 3 months. Concentrations of TFV in vaginal fluid (VF), and TFV and TFV-diphosphate (TFV-DP) in vaginal tissue, and modeled PD against HIV-1 in vitro were measured before and after treatment.ResultsThere were no clinically significant changes in relative abundance of vaginal bacterial phylotypes from pre-insertion baseline at any month among active and placebo IVR users. There were no significant changes in community state type (CST) with IVR use. Participants with diverse, anaerobic CST IVA/B microbiota had higher in vivo release of TFV from the IVR compared to women with Lactobacillus-dominated (LbD) microbiota, who had expected in vivo TFV release rates. Median VF TFV concentrations were significantly higher among women with CST IVA/B microbiota in months 1 (3,135 ng/mg VF) and 2 (3,800 ng/mg). Women with LbD microbiota had significantly higher median VF TFV concentration (1,423 ng/mg) and median TFV (103 ng/mg) and TFV-DP (5,877 fmol/mg) tissue concentrations versus women with CST IVA/B microbiota at month 3. All women demonstrated a significant increase from pre-insertion baseline of in vitro HIV-1 inhibition by VF (p values <0.05). PD differences in tissue according to CST, however, were not statistically significant.ConclusionTFV/LNG IVR use did not change the vaginal microbiota nor increase the incidence of CST IVA/B. Vaginal microbiota, and in particular CST IVA/B, possibly through increased vaginal pH, impacted in vivo TFV release and cervicovaginal (CV) PK, but both PK and PD data suggest CV protection against HIV-1.Clinical trial registrationClinicalTrials.gov (#NCT03279120).
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Project description:The onset of menopause is accompanied by a dramatic increase in reported symptoms of vaginal dryness, soreness, irritation or itching, pain with intercourse and bleeding after intercourse. Collectively these affect 25-50% of women of post-menopausal age and significantly impact their quality of life. To examine how gene expression differs between these groups, surface vaginal epithelial cells were collected from postmenopausal women suffering from vaginal dryness and appropriate controls not suffering from dryness. Affymetrix GeneChip Human 1.0 ST microarrays were performed on RNA isolated from ten participants.
2011-11-12 | GSE26761 | GEO
Project description:BackgroundMenopause, a natural phase in a woman's life, often adversely affects physical, mental, sexual, and emotional well-being due to low estrogen levels. This study examines the impact of vaginal ovules with tocopherol acetate (Filme Gyno-V® ovules, manufactured by Panin Srl and distributed by Hulka Srl, Italy), 500 mg per ovule, on vaginal health in pre- and menopausal women.MethodsFifty women aged 50-70 were divided into menopausal (28) and premenopausal (22) cohorts and treated with the ovules for two weeks, with assessments before and after treatment.ResultsThe findings showed that distressing symptoms of vaginal atrophy, such as dryness, itching, and pain during intercourse, were resolved post-treatment. A molecular analysis revealed a reduction in Escherichia coli in both cohorts and an increase in three species of Lactobacillus in premenopausal patients.ConclusionsThis study concludes that Filme Gyno-V ovules may benefit vaginal health by alleviating atrophy symptoms and promoting healthy vaginal microbiota.
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