Estrogen Receptor-beta phytoSERMs for Management of Menopause and Age-Associated

用于管理更年期和与年龄相关的雌激素受体-β phytoSERM

基本信息

批准号：
8079024
负责人：
LON S SCHNEIDER
金额：
$ 53.49万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8079024
关键词：
Adverse effects Adverse event Age Age-associated memory impairment Alzheimer&apos s Disease Benign Biological Availability Biological Markers Clinical Cognition Cognitive aging Complex Dementia Development Dose Double-Blind Method Drug Formulations Drug Kinetics Effectiveness Estrogen Receptor 2 Estrogen Receptor beta Estrogen Receptors Estrogen Therapy Estrogens Event Failure Functional disorder Future Genistein Goals Health Benefit Hot flushes Human Impaired cognition Individual Differences Isoflavones Knowledge Lead Lipid Peroxidation Mediating Memory Menopause Methods Mitochondria Moods Nutraceutical Outcome Ovarian Participant Pathologic Peripheral Pharmacodynamics Phase Phytoestrogens Pilot Projects Placebo Control Placebos Plants Postmenopause Preparation Production Program Development Randomized Regulation Reporting Risk Safety Selective Estrogen Receptor Modulators Severities Symptoms Syndrome Therapeutic Effect Time Tissues Vasomotor Well in self Woman Women&apos s Health age related base clinically relevant cognitive function daidzein design dietary supplements drug development efficacy trial equol experience improved new therapeutic target older men older women pilot trial placebo controlled study public health relevance receptor reproductive response soy soy protein isolate therapy development

项目摘要

DESCRIPTION (provided by applicant): Selective estrogen receptor-2 (ER2) targeting may be a novel therapeutic target for the development of therapies for a range of conditions including cognitive impairment and age- related ovarian failure (menopause). There are plausible mechanisms by which ER2 receptor stimulation could lead to improved cognition, feelings of well being, reduced risks for cognitive impairment, and improved vasomotor symptoms. A formulation composed of rationally-selected ER2-selective phytoestrogens (phytoSERMs) was developed that provides a greater effect than the various nutraceuticals that are mixed with both ER1 and ER2 selective components. This new formulation is composed of rationally-defined content that induces synergistic rather than antagonistic effects on estrogen receptors and could likely generate salutary therapeutic effects. The formulation enhances ER2 responses by adding equol to genistein and daidzein moderating potential influences of inter- individual differences in the production of equol. Three major potential advantages of the formulation are: (1) reduction of antagonistic interactions that occur in complex soy-derived isoflavone preparations; (2) minimization of adverse effects associated with ER1 activation in reproductive tissues; (3) potential health benefits in pathologic conditions mediated by ER2. Thus, it may serve as an alternative to current estrogen therapies. We are proposing a phase I to IIa pilot development program for this ER2 specific phytoSERM combination for post-menopausal women in the 50 year-old range as the first to human studies. The phase I bridging study uses ascending doses in 3 consecutive panels of 9 participants to assess tolerability, pharmacokinetics, and potential safety with 4 weeks exposures. The phase IIa proof of concept dose-ranging, placebo-controlled trial will assess tolerability, safety, and potential efficacy over 12 weeks. Given that soy isoflavone extracts are available as dietary supplements, and that the compounds are 'generally recognized as safe' (GRAS, under FDA regulations), we expect this phytoSERM combination to be very well tolerated with a benign adverse event profile over 12 weeks. Because soy derived isoflavones sold as dietary supplements were not subject to formal drug development, and that this is a new combination of phytoSERMs, we believe that a careful, stepwise development approach for the phytoSERMs will provide systematic information, better benefit clinical knowledge, and provide a platform for future development. PUBLIC HEALTH RELEVANCE: One of the largest unmet needs in menopausal women's health is an estrogen therapy that is both safe and effective. We have developed a formulation of phytoestrogenic molecules, that we term PhytoSERMs, which targets estrogen receptor beta. This study will determine the best dose, safety and tolerance of PhytoSERMs in peri to menopausal women experiencing hot flashes. We will also conduct a pilot analysis to determine the efficacy of PhytoSERMs to significantly reduce hot flashes.

描述（由申请人提供）：选择性雌激素受体 2 (ER2) 靶向可能是开发治疗一系列疾病的新治疗靶点，包括认知障碍和年龄相关的卵巢功能衰竭（更年期）。 ER2 受体刺激可能通过某些机制改善认知、幸福感、降低认知障碍风险并改善血管舒缩症状。我们开发了一种由合理选择的 ER2 选择性植物雌激素 (phytoSERM) 组成的配方，其效果比与 ER1 和 ER2 选择性成分混合的各种营养保健品更好。这种新配方由合理定义的成分组成，可对雌激素受体产生协同而非拮抗作用，并可能产生有益的治疗效果。该制剂通过向金雀异黄素和大豆黄酮中添加雌马酚来调节雌马酚产生的个体间差异的潜在影响，从而增强 ER2 反应。该配方的三个主要潜在优点是：（1）减少复杂的大豆异黄酮制剂中发生的拮抗相互作用； (2) 最大限度地减少与生殖组织中 ER1 激活相关的不利影响； (3) ER2介导的病理状况的潜在健康益处。因此，它可以作为当前雌激素疗法的替代品。我们正在提议针对 50 岁范围内绝经后女性的这种 ER2 特异性 phytoSERM 组合进行 I 至 IIa 期试点开发计划，作为首次人体研究。 I 期桥接研究在由 9 名参与者组成的 3 个连续小组中使用递增剂量，以评估 4 周暴露的耐受性、药代动力学和潜在安全性。 IIa 期概念验证剂量范围、安慰剂对照试验将评估 12 周内的耐受性、安全性和潜在疗效。鉴于大豆异黄酮提取物可作为膳食补充剂使用，并且这些化合物“普遍被认为是安全的”（根据 FDA 规定，GRAS），我们预计这种 phytoSERM 组合具有良好的耐受性，并且在 12 周内不会出现良性不良事件。由于作为膳食补充剂出售的大豆异黄酮并未经过正式的药物开发，而且这是 phytoSERM 的新组合，因此我们相信，对 phytoSERM 采取谨慎、逐步的开发方法将提供系统信息，更好地有益于临床知识，并提供未来发展的平台。公共卫生相关性：更年期妇女健康中最大的未满足需求之一是安全有效的雌激素疗法。我们开发了一种植物雌激素分子配方，我们称之为 PhytoSERM，它以雌激素受体 β 为目标。这项研究将确定 PhytoSERM 在经历潮热的围绝经期女性中的最佳剂量、安全性和耐受性。我们还将进行试点分析，以确定 PhytoSERM 显着减少潮热的功效。