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Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor ?-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

ABSTRACT: OBJECTIVE:Selected estrogen receptor ?-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) ?, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women. METHODS:Eighteen women aged 45 to 60 years from a 12-week clinical trial evaluating cognitive performance and vasomotor symptoms were randomly assigned to placebo, 50?mg, or 100?mg phytoSERM treatment groups. Plasma levels of the three parent phytoestrogens and their metabolites were measured before and at 2, 4, 6, 8, and 24?hours after ingestion by isotope dilution high-performance liquid chromatography (HPLC) electrospray ionization tandem mass spectrometry. RESULTS:Plasma concentrations of genistein, daidzein, and S-equol peaked at 9, 6, and 4?hours, respectively, for the 50-mg dose, and at 6, 6, and 5?hours, respectively, for the 100-mg dose. The maximum concentration (Cmax) and area under the curve (AUC) for the three parent compounds were greater in the 100-mg dose group, indicating a dose-dependent change in concentration with the phytoSERM treatment. No adverse events were elicited. CONCLUSIONS:A single-dose oral administration of the phytoSERM formulation was well-tolerated and did not elicit any adverse events. It was rapidly absorbed, reached high plasma concentrations, and showed a linear dose-concentration response in its pharmacokinetics. These findings are consistent with previously reported parameters for each parent compound (Clinicaltrials.gov NCT01723917).

SUBMITTER: Hernandez G

PROVIDER: S-EPMC5771891 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

Hernandez Gerson G Zhao Liqin L Franke Adrian A AA Chen Yu-Ling YL Mack Wendy J WJ Brinton Roberta D RD Schneider Lon S LS

Menopause (New York, N.Y.) 20180201 2

<h4>Objective</h4>Selected estrogen receptor β-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) β, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women.<h4>Me ...[more]

PMID: 28926513

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Project description:Our recent developments have yielded a novel phytoestrogenic formulation, referred to as the phyto-?-SERM formulation, which exhibits an 83-fold binding selectivity for the estrogen receptor subtype ? (ER?) over ER?. Earlier studies indicate that the phyto-?-SERM formulation is neuroprotective and promotes estrogenic mechanisms in the brain while devoid of feminizing activity in the periphery. Further investigation in a mouse model of human menopause indicates that chronic exposure to the phyto-?-SERM formulation at a clinically relevant dosage prevents/alleviates menopause-related climacteric symptoms. This study assessed the efficacy, in an early intervention paradigm, of the phyto-?-SERM formulation in the regulation of early stages of physical and neurological changes associated with Alzheimer's disease (AD) in a female triple transgenic mouse model of AD. Results demonstrated that, when initiated prior to the appearance of AD pathology, a 9-month dietary supplementation with the phyto-?-SERM formulation promoted physical health, prolonged survival, improved spatial recognition memory, and attenuated amyloid-? deposition and plaque formation in the brains of treated AD mice. In comparison, dietary supplementation of a commercial soy extract preparation showed no effect on cognitive measures, although it appeared to have a positive impact on amyloid pathology. In overall agreement with the behavioral and histological outcomes, results from a gene expression profiling analysis offered insights on the underlying molecular mechanisms associated with the two dietary treatments. In particular, the data suggests that there may be a crosstalk between ER? and glycogen synthase kinase 3 signaling pathways that could play a role in conferring ER?-mediated neuroprotection against AD. Taken together, these results support the therapeutic potential of the phyto-?-SERM formulation for prevention and/or early intervention of AD, and warrants further investigations in human studies.

Project description:IntroductionAzithromycin has been given for tropical infectious diseases such as trachoma and yaws by mass drug administration (MDA). As well as controlling the infectious disease in question, MDA may have a beneficial effect in reducing mortality in young children. However, the dose, formulation, frequency and duration of azithromycin used in certain infectious diseases may vary in different studies, and these differences may have impacts on the effectiveness of azithromycin MDA. Furthermore, whether the dose, formulation, frequency and duration are associated with the effectiveness of azithromycin for reducing child mortality-if indeed this effect can be confirmed-remain unknown. In this study, we will investigate whether different strategies such as different dose, formulation, frequency and duration affect the effectiveness of azithromycin MDA on the prevalence of certain infectious diseases or child mortality.Methods and analysisA narrative systematic review will be conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov and WHO International Clinical Trials Registry Platform will be searched. No language restrictions will be applied. All randomised/quasi-controlled trials, observational studies (cross-sectional studies, cohort studies and case-control studies), case series and registered protocols will be considered. Dose, duration, frequency, rounds and formulations of azithromycin used in MDA will be collected and reviewed. The outcomes will be disease prevalence/control in children and child mortality. Data from the individual studies will not be pooled.Ethics and disseminationFormal ethical approval is not required since data will be collected from published studies. This systematic review will be published in a peer-reviewed journal and presented at conference meetings.Prospero registration numberCRD42018114902.

Project description:BACKGROUND:Osteoporosis affects elderly patients of both sexes. It is characterized by an increased fracture risk due to defective remodeling of the bone microarchitecture. It affects in particular postmenopausal women due to their decreased levels of estrogen. Preclinical studies with animals demonstrated that loss of estrogen had a negative effect on bone healing and that increasing the estrogen level led to a better bone healing. We asked whether increasing the estrogen level in menopausal patients has a beneficial effect on bone mineral density (BMD) during callus formation after a bone fracture. METHODS:To investigate whether estrogen has a beneficial effect on callus BMD of postmenopausal patients, we performed a prospective double-blinded randomized study with 76 patients suffering from distal radius fractures. A total of 31 patients (71.13?years ±11.99) were treated with estrogen and 45 patients (75.62?years ±10.47) served as untreated controls. Calculated bone density as well as cortical bone density were determined by peripheral quantitative computed tomography (pQCT) prior to and 6 weeks after the surgery. Comparative measurements were performed at the fractured site and at the corresponding position of the non-fractured arm. RESULTS:We found that unlike with preclinical models, bone fracture healing of human patients was not improved in response to estrogen treatment. Furthermore, we observed no dependence between age-dependent bone tissue loss and constant callus formation in the patients. CONCLUSIONS:Transdermally applied estrogen to postmenopausal women, which results in estrogen levels similar to the systemic level of premenopausal women, has no significant beneficial effect on callus BMD as measured by pQCT, as recently shown in preclinical animal models. TRIAL REGISTRATION:Low dose estrogen has no significant effect on bone fracture healing measured by pQCT in postmenopausal women, DRKS00019858 . Registered 25th November 2019 - Retrospectively registered. Trial registration number DRKS00019858 .

Dataset Information

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor ?-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

Publications

Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.

Similar Datasets

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