Mechanisms of action of currently available woman-controlled, vaginally administered, non-hormonal contraceptive products
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ABSTRACT:
SUBMITTER: Chappell B
PROVIDER: S-EPMC9272165 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveIn AIDS Clinical Trials Group study A5316, efavirenz lowered plasma concentrations of etonogestrel and ethinyl estradiol, given as a vaginal ring, while atazanavir/ritonavir increased etonogestrel and lowered ethinyl estradiol concentrations. We characterized the pharmacogenetics of these interactions.MethodsIn A5316, women with HIV enrolled into control (no antiretrovirals), efavirenz [600 mg daily with nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs)], and atazanavir/ritonavir (300/100 mg daily with NRTIs) groups. On day 0, a vaginal ring was inserted, releasing etonogestrel/ethinyl estradiol 120/15 μg/day. Intensive plasma sampling for antiretrovirals was obtained on days 0 and 21, and single samples for etonogestrel and ethinyl estradiol on days 7, 14, and 21. Seventeen genetic polymorphisms were analyzed.ResultsThe 72 participants in this analysis included 25, 24 and 23 in the control, efavirenz, and atazanavir/ritonavir groups, respectively. At day 21 in the efavirenz group, CYP2B6 genotype was associated with increased plasma efavirenz exposure (P = 3.2 × 10), decreased plasma concentrations of etonogestrel (P = 1.7 × 10), and decreased ethinyl estradiol (P = 6.7 × 10). Compared to controls, efavirenz reduced median etonogestrel concentrations by at least 93% in CYP2B6 slow metabolizers versus approximately 75% in normal and intermediate metabolizers. Efavirenz reduced median ethinyl estradiol concentrations by 75% in CYP2B6 slow metabolizers versus approximately 41% in normal and intermediate metabolizers.ConclusionCYP2B6 slow metabolizer genotype worsens the pharmacokinetic interaction of efavirenz with hormonal contraceptives administered by vaginal ring. Efavirenz dose reduction in CYP2B6 slow metabolizers may reduce, but will likely not eliminate, this interaction.
| S-EPMC7398416 | biostudies-literature
Project description:BackgroundDrug-drug interactions between orally administered antiretroviral therapy (ART) and hormones released from an intravaginal ring are not known. We hypothesised that ART containing either efavirenz or ritonavir-boosted atazanavir would alter plasma concentrations of vaginally administered etonogestrel and ethinylestradiol but that ART concentrations would be unchanged during use of an intravaginal ring.MethodsWe did a parallel, three-group, pharmacokinetic evaluation at HIV clinics in Asia (two sites), South America (five), sub-Saharan Africa (three), and the USA (11) between Dec 30, 2014, and Sept 12, 2016. We enrolled women with HIV who were either ART-naive (control group; n=25), receiving efavirenz-based ART (n=25), or receiving atazanavir-ritonavir-based ART (n=24). Women receiving ART were required to be on the same regimen for at least 30 days, with 400 copies or less per mL of plasma HIV-1 RNA; women not receiving ART had CD4 counts of 350 cells per μL or less. We excluded participants who had a bilateral oophorectomy or conditions that were contraindicated in the intravaginal ring product labelling. An intravaginal ring releasing etonogestrel and ethinylestradiol was inserted at entry (day 0). Single plasma samples for hormone concentrations were collected on days 7, 14, and 21 after intravaginal ring insertion. The primary outcome was the plasma concentration of etonogestrel and ethinylestradiol on day 21. Etonogestrel and ethinylestradiol concentrations were compared between each ART group and the control group by geometric mean ratio (GMR) with 90% CIs and Wilcoxon rank-sum test. As secondary outcomes, efavirenz or ritonavir-boosted atazanavir concentrations were assessed by 8-h intensive pharmacokinetic sampling at entry before intravaginal ring insertion and before intravaginal ring removal on day 21. Antiretroviral areas under the concentration-time curve (AUC0-8 h) were compared before and after intravaginal ring insertion by GMR (90% CI) and Wilcoxon signed-rank test. This study is registered with ClinicalTrials.gov, number NCT01903031.FindingsBetween Dec 30, 2014, and Sept 12, 2016, we enrolled 84 participants in the study; ten participants were excluded from the primary hormone analysis. 74 participants met the primary endpoint: 25 in the control group, 25 in the efavirenz group, and 24 in the atazanavir group. On day 21 of intravaginal ring use, participants receiving efavirenz had 79% lower etonogestrel (GMR 0·21, 90% CI 0·16-0·28; p<0·0001) and 59% lower ethinylestradiol (0·41, 0·32-0·52; p<0·0001) concentrations compared with the control group. By contrast, participants receiving ritonavir-boosted atazanavir had 71% higher etonogestrel (1·71, 1·37-2·14; p<0·0001), yet 38% lower ethinylestradiol (0·62, 0·49-0·79; p=0·0037) compared with the control group. The AUC0-8 h of efavirenz or atazanavir did not differ between the groups.InterpretationHormone exposure was significantly lower when an intravaginal ring contraceptive was combined with efavirenz-based ART. Further studies designed to examine pharmacodynamic endpoints, such as ovulation, when intravaginal ring hormones are combined with efavirenz are warranted.FundingNational Institutes of Health, through the AIDS Clinical Trials Group and the International Maternal Pediatric Adolescent AIDS Clinical Trials Network, National Institute of Allergy and Infectious Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.
| S-EPMC6765389 | biostudies-literature
Project description:AIMS:A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film. METHODS:A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions. RESULTS:The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29?079 and 33?067 mg h l-1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l-1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range. CONCLUSIONS:HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female-controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated.
| S-EPMC6089833 | biostudies-literature
Project description:Neuroendocrine neoplasms (NEN) are frequently characterized by a high propensity for metastasis to the liver, which appears to be a dominant site of distant-stage disease, affecting quality of life and overall survival. Liver surgery with the intention to cure is the treatment of choice for resectable neuroendocrine liver metastases (NELM), aiming to potentially prolong survival and ameliorate hormonal symptoms refractory to medical control. Surgical resection is indicated for patients with NELM from well-differentiated NEN, while its feasibility and complexity are largely dictated by the degree of liver involvement. As a result of advances in surgical techniques over the past decades, complex 1- and 2-stage, or repeat liver resections are performed safely and effectively by experienced surgeons. Furthermore, liver transplantation for the treatment of NELM should be anchored in a multimodal and multidisciplinary therapeutic strategy and restricted only to highly selected individual cases. A broad spectrum of interventional radiology treatments for NELM have recently been available, with expanding indications that are more applicable, as they are less limited by patient- and tumor-related parameters, being therefore important adjuncts or alternatives to surgery. Overall, liver-targeted treatment modalities may precede the administration of systemic molecular targeted agents and chemotherapy for patients with liver-dominant metastatic disease; these appear to be a crucial component of multimodal management of patients with NEN. In the present review, we discuss surgical and non-surgical liver-targeted treatment approaches for NELM, each complementing the other, with a view to assisting physicians in optimizing multimodal NEN patient care.
| S-EPMC7903580 | biostudies-literature
Project description:In normal pregnancy, the egg is fertilized in the fallopian tube. It later moves into the uterus, where it implants into the uterine endometrium. Therefore, implantation of the fertilized egg into the endometrium is not observed in many women using contraceptives. However, if the fallopian tubes are diseased or abnormal, the fertilized egg cannot travel to the endometrium. Thus, the fertilized egg is implanted in tissues other than the uterus, resulting in an ectopic pregnancy. In most cases of ectopic pregnancy, the fertilized egg is implanted into the left or right fallopian tube or in tissues other than the fallopian tubes such as the ovary. With laparoscopic surgery, the scars are small, and the pain and physical burden are also much lesser than those with open surgery; thus, the patient can be rehabilitated immediately. Laparoscopic surgery is preferred for the termination of ectopic pregnancies because the patients recovered quickly physically after surgery and can be discharged in a short period. This paper presents our experience in treating a 37-year-old woman who had a tubal pregnancy despite using a contraceptive. Contrast-enhanced magnetic resonance imaging showed a gestational sac within the right fallopian tube. Laparoscopic surgery was performed to resect the right fallopian tube. Pathological examination suggested that the ectopic pregnancy occurred at the organogenesis stage 9 weeks after fertilization. The pathological findings revealed subpopulations of cells from the ectoderm that were separated from other cells and more specifically formed spinal and ovarian structures. The implantation of the fertilized egg into the endometrium is not observed in many women using contraceptives. However, in rare cases, ectopic pregnancy occurs in women using contraceptives; thus, caution is necessary in diagnosis and treatment. This report presents valuable surgical pathological findings from such a rare case of ectopic pregnancy to understand the differentiation into each tissue during organogenesis.
| S-EPMC10416193 | biostudies-literature
Project description:This chapter discusses the mechanisms of action of hormonal male contraception, which suppresses the hypothalamic-pituitary-testis axis. When the intratesticular concentration of testosterone is subsequently suppressed to adequately low concentrations, spermatogenesis is arrested. Androgens are a necessary hormonal male contraceptive component because they not only suppress the hypothalamic-pituitary-testis axis, but also provide the male hormone necessary to maintain peripheral androgen functions. Past studies using testosterone alone and testosterone combined with progestins demonstrated contraceptive efficacy in the female partner at rates similar to combined hormonal female methods. Newer hormonal male contraceptive formulations and the alternative routes of administration are discussed, along with potential barriers, challenges, and opportunities for hormonal male contraceptive development. Novel methods that are safe, effective, reversible, user-friendly, and coitus-independent are intrinsic to equitably meet the various needs and limitations of an increasingly diverse population.
| S-EPMC7375909 | biostudies-literature
Project description:The first complete genome that was sequenced at the beginning of the sequencing era was that of a phage, since then researchers throughout the world have been steadily describing and publishing genomes from a wide array of phages, uncovering the secrets of the most abundant and diverse biological entities known to man. Currently, we are experiencing an unprecedented rate of novel bacteriophage discovery, which can be seen from the fact that the amount of complete bacteriophage genome entries in public sequence repositories has more than doubled in the past 3 years and is steadily growing without showing any sign of slowing down. The amount of publicly available phage genome-related data can be overwhelming and has been summarized in literature before but quickly becomes out of date. Thus, the aim of this paper is to briefly outline currently available phage diversity data for public acknowledgment that could possibly encourage and stimulate future "depth" studies of particular groups of phages or their gene products.
| S-EPMC7658105 | biostudies-literature
Project description:BACKGROUND/OBJECTIVES:Experiments in animal models have shown a positive association between in utero exposure to pharmacologic sex hormones and offspring obesity. The developmental effects of such hormones on human obesity are unknown. SUBJECTS/METHODS:Using data from a large, prospective pregnancy cohort study (n=19?652), with linkage to a national prescription registry, we evaluated the association between use of hormonal contraceptives before and after conception (defined from dispensed prescription data and characterized by last date of use relative to conception, 12 to >4 months before (n=3392), 4 to >1 months before (n=2541), 1 to >0 months before (n=2997) and 0-12 weeks after (n=567)) in relation to offspring overweight or obesity at age 3 years. RESULTS:We observed a weak, inverse association between early pregnancy use of a combination oral contraceptive and offspring overweight or obesity at age 3 (adjusted odds ratio (OR): 0.75, 95% confidence interval (CI): 0.53, 1.08) and a positive, but imprecise, association with use of a progestin-only oral contraceptive in early pregnancy (adjusted OR: 1.26, 95% CI: 0.79, 2.02). In general, no association was observed between the use of a hormonal contraceptive before conception and offspring overweight or obesity. A sensitivity analysis comparing combination oral contraceptive users in early pregnancy to other unplanned pregnancies without hormonal contraceptive use further strengthened the inverse association (adjusted OR: 0.70, 95% CI: 0.48, 1.02). Other sensitivity analyses were conducted to evaluate the robustness of the associations observed given varying assumptions. CONCLUSIONS:Pharmacologic sex hormones in early pregnancy may be inversely or positively associated with offspring overweight or obesity at age 3, depending on the specific formulation used. The present study provides support for the potential for environmental sources of hormonally active agents to exert developmental effects.
| S-EPMC4365991 | biostudies-literature
Project description:To identify biomarkers of hormonal contraceptive (HC) use in urine and saliva, we conducted a pilot study with 30 women initiating levonorgestrel (LNG) containing combined oral contraceptives (COCs) or depot medroxyprogesterone acetate (DMPA) (15/group). Based on established COC pharmacokinetics, we collected serum and urine samples before COC ingestion and during Days one and three of use, or before DMPA injection and on Days 21 and 60 post-injection. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to measure serum/urine LNG and MPA. LNG was undetectable at baseline (specificity 100%); post ingestion, most urine samples had detectable LNG levels (sensitivity: 80% 6 h post Dose one, 93% 6 h post Dose three). We used a DetectX LNG immunoassay kit and showed 100% sensitivity measuring urine LNG. Urine MPA levels were undetectable in 14/15 women at baseline (specificity 91%); post-injection all urine samples had detectable MPA levels (sensitivity: 100% days 21 and 60). Results suggest urine sampling can be used to identify a biomarker of LNG and MPA use. Based on evidence from other steroidal hormonal studies showing changes affecting the transcriptome profile of saliva at 24 h, we used the same (COC, DMPA) timepoints to collect saliva. We performed transcriptome analysis and detected several differentially expressed genes in DMPA users' saliva on Days 21 and 60 compared to baseline; none among COC users. We plan further research of differential gene expression in saliva as a HC biomarker of DMPA use, and will explore longer periods of COC use and saliva collection times, and application of microRNA sequencing to support using saliva as a COC biomarker.
| S-EPMC9816169 | biostudies-literature
Project description:BackgroundDifferential diagnosis (DDX) generators are computer programs that generate a DDX based on various clinical data.ObjectiveWe identified evaluation criteria through consensus, applied these criteria to describe the features of DDX generators, and tested performance using cases from the New England Journal of Medicine (NEJM©) and the Medical Knowledge Self Assessment Program (MKSAP©).MethodsWe first identified evaluation criteria by consensus. Then we performed Google® and Pubmed searches to identify DDX generators. To be included, DDX generators had to do the following: generate a list of potential diagnoses rather than text or article references; rank or indicate critical diagnoses that need to be considered or eliminated; accept at least two signs, symptoms or disease characteristics; provide the ability to compare the clinical presentations of diagnoses; and provide diagnoses in general medicine. The evaluation criteria were then applied to the included DDX generators. Lastly, the performance of the DDX generators was tested with findings from 20 test cases. Each case performance was scored one through five, with a score of five indicating presence of the exact diagnosis. Mean scores and confidence intervals were calculated.Key resultsTwenty three programs were initially identified and four met the inclusion criteria. These four programs were evaluated using the consensus criteria, which included the following: input method; mobile access; filtering and refinement; lab values, medications, and geography as diagnostic factors; evidence based medicine (EBM) content; references; and drug information content source. The mean scores (95% Confidence Interval) from performance testing on a five-point scale were Isabel© 3.45 (2.53, 4.37), DxPlain® 3.45 (2.63-4.27), Diagnosis Pro® 2.65 (1.75-3.55) and PEPID™ 1.70 (0.71-2.69). The number of exact matches paralleled the mean score finding.ConclusionsConsensus criteria for DDX generator evaluation were developed. Application of these criteria as well as performance testing supports the use of DxPlain® and Isabel© over the other currently available DDX generators.
| S-EPMC3270234 | biostudies-literature