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P2‐028: 2019 ALZHEIMER'S DRUG PIPELINE REPORT: THE PATH TO A CURE
Author(s) -
Morgan Dave
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.06.1250
Subject(s) - clinical trial , drug development , pipeline (software) , medicine , pharmaceutical industry , drug , operations research , medical education , computer science , pharmacology , engineering , pathology , programming language
Background: Women account for 68% of all cases of Alzheimer’s disease (AD). Estrogen and hormone replacement therapies (HRT) begun at the time of menopause transition have been associated with reduced risk and delayed onset of AD. However, adverse outcomes of HRT have led to increasing number of women declining its use but seeking non-pharmaceutical alternatives. The search for a safe approach to promote estrogenic signaling in the brain, without eliciting adverse effects, has focused on the development of tissue-selective estrogen receptor modulators (SERMs). Selective estrogen receptor-b (ER-b) targeting has been attempted in the development of therapies for a range of conditions including cognitive impairment and menopausal symptoms. PhytoSERM, a preparation of genistein, daidzein, and S-equol, has a 83-fold selective affinity for (ER-b) and may promote neuronal survival and estrogenic mechanisms in the brain without having feminizing activity in the periphery. The objective of this study was to assess the safety, tolerability and single-dose pharmacokinetics of the phytoSERM formulation in periand postmenopausal women. Methods: Eighteen women aged 45-60 years from a 12week clinical trial evaluating cognitive performance and vasomotor symptoms were randomly assigned to placebo, 50mg, or 100mg phytoSERM treatment groups. Plasma levels of the 3 parent phytoestrogens and their metabolites were measured before and at 2, 4, 6, 8 and 24 hours after ingestion by isotope dilution HPLC electrospray ionization tandem mass spectrometry. Results: Plasma concentrations of genistein, daidzein and S-equol peaked at 9, 6 and 4 h, respectively for the 50mg dose, and at 6, 6 and 5 h, respectively for the 100 mg dose. The maximum concentration (Cmax) and area under the curve (AUC) for the 3 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: The phytoSERM combination was well tolerated, appeared without adverse effects, and exhibited a favorable pharmacokinetic profile. After single oral administration of 50 and 100mg tablets of the phytoSERM formulation, the phytoestrogens were rapidly absorbed, reached high plasma concentrations, and showed a dose proportional increase in concentration exposures in its pharmacokinetics.