Estrogen Receptor-beta phytoSERMs for Management of Menopause and Memory Decline

描述(由申请人提供)：选择性雌激素受体-2(ER2)靶向可能是一种新的治疗靶点，可用于开发一系列疾病的治疗方法，包括认知障碍和与年龄相关的卵巢衰竭(更年期)。ER2受体刺激可以改善认知，改善幸福感，降低认知障碍的风险，改善血管舒缩症状，这是有道理的机制。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，其效果比各种营养食品同时与ER1和ER2选择性成分混合的效果更好。这一新配方由合理定义的内容组成，对雌激素受体产生协同作用而不是拮抗作用，并可能产生有益的治疗效果。该配方通过向染料木素和大豆苷元中添加马儿酚来增强ER2反应，缓解马儿酚生产过程中个体间差异的潜在影响。该配方的三个主要潜在优势是：(1)减少复杂的大豆异黄酮制剂中出现的拮抗相互作用；(2)最大限度地减少与ER1在生殖组织中激活有关的不良影响；(3)在ER2介导的病理条件下潜在的健康益处。因此，它可以作为目前雌激素疗法的替代方案。我们提出了一项针对50岁绝经后妇女的ER2特异性植物-SERM组合的I-IIa阶段试点开发计划，作为首次人体研究。I期桥接研究在9名参与者的3个连续小组中使用递增剂量来评估4周暴露的耐受性、药代动力学和潜在安全性。IIa阶段的概念验证、剂量范围、安慰剂对照试验将在12周内评估耐受性、安全性和潜在疗效。鉴于大豆异黄酮萃取物可用作膳食补充剂，而且这些化合物“普遍被认为是安全的”(根据FDA的法规，GRAS)，我们预计这种植物SERM组合在12周内将具有良好的耐受性和良性的不良事件特征。由于作为膳食补充剂出售的大豆异黄酮不受正式药物开发的影响，而且这是一种植物SERM的新组合，我们相信谨慎、循序渐进的植物SERM开发方法将提供系统的信息，更好地惠及临床知识，并为未来的开发提供平台。 公共卫生相关性：更年期妇女健康中最大的未得到满足的需求之一是安全有效的雌激素疗法。我们已经开发了一种植物雌激素分子的配方，我们称之为植物SERM，它针对雌激素受体β。这项研究将确定发生潮热的绝经妇女围绝经期服用PhytoSERM的最佳剂量、安全性和耐受性。我们还将进行一项试验性分析，以确定植物SERM显著减少潮热的有效性。

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.