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

• 批准号: 7785854
• 负责人: LON S SCHNEIDER
• 金额: $ 68.67万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 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/7785854
• 关键词: Adverse effects; Adverse event; Age; Age-associated memory impairment; Alzheimer' s Disease; Benign; Biological Availability; Biological Markers; Clinical; Cognition; 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; 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' s Health; base; clinically relevant; cognitive function; daidzein; design; dietary supplements; drug development; efficacy trial; equol; experience; improved; men; new therapeutic target; older women; pilot trial; placebo controlled study; public health relevance; receptor; reproductive; response; soy; soy protein isolate; therapy development

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）靶向可能是用于开发疗法的新型治疗靶标，包括一系列疾病，包括认知障碍和与年龄相关的卵巢衰竭（绝经）。 ER2受体刺激有可能导致认知，健康的感觉，认知障碍的风险降低以及增加的血管舒缩症状。 开发了由合理选择的ER2选择性植物雌激素（植物剂）组成的配方，该配方比与ER1和ER2选择性成分混合的各种营养素提供了更大的效果。这种新的配方由理性定义的含量组成，这些含量诱导了对雌激素受体的协同作用而不是拮抗作用，并且可能产生有益的治疗作用。该公式通过向染料木黄酮和大吉素增加雌激素来增强ER2反应，从而调节了雌性产生中个体差异的潜在影响。该配方的三个主要潜在优势是：（1）在复杂的大豆衍生的异黄酮制剂中减少拮抗相互作用； （2）最小化与生殖组织中ER1激活相关的不良反应； （3）ER2介导的病理状况中的潜在健康益处。因此，它可以作为当前雌激素疗法的替代方法。 我们正在为这项50岁范围内的期限后妇女提供IIA试验性开发计划的I阶段IIA试点开发计划，作为人类研究的首次研究。第一阶段的桥接研究使用9位参与者的3个连续面板中使用上升剂量来评估耐受性，药代动力学和潜在安全性，并进行4周的暴露。 IIA期概念剂量范围，安慰剂对照试验的概念证明将在12周内评估耐受性，安全性和潜在疗效。鉴于大豆异黄酮提取物可作为饮食补充剂提供，并且这些化合物“通常被认为是安全的”（GRAS，根据FDA法规），我们希望这种植物剂组合在12周内具有良性不良事件的耐受性耐受性。因为出售的大豆衍生的异黄酮不受正式的药物开发的影响，这是植物剂的新组合，我们认为，针对植物血剂的仔细的，逐步开发的方法将提供系统的信息，更好地利益临床知识，并为未来的发展提供一个平台。 公共卫生相关性：绝经女性健康中最大的未满足需求之一是一种既安全有效的雌激素疗法。我们已经开发了一种植物源性分子的公式，即我们称植物剂为靶向雌激素受体β。这项研究将确定植物剂对春季的最佳剂量，安全性和耐受性。我们还将进行试点分析，以确定植物剂的疗效，以显着降低热闪光。