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，用于开发一系列疾病的治疗方法，包括认知障碍和年龄相关性卵巢功能衰竭（更年期）。ER2受体刺激可能导致认知改善、感觉良好、降低认知障碍风险和改善血管舒缩症状的机制似乎是合理的。一种由合理选择的ER2选择性植物雌激素（phytoSERMs）组成的配方被开发出来，比混合了ER1和ER2选择性成分的各种营养保健品提供更大的效果。这种新配方由合理定义的成分组成，对雌激素受体产生协同而非拮抗作用，可能产生有益的治疗效果。该配方通过在染料木素和大豆苷元中加入雌马酚来增强ER2反应，从而调节雌马酚产生过程中个体间差异的潜在影响。该配方的三个主要潜在优点是：(1)减少了复杂的大豆异黄酮制剂中的拮抗相互作用；(2)尽量减少生殖组织中ER1激活相关的不良影响；(3) ER2介导的病理条件下的潜在健康益处。因此，它可以作为目前雌激素治疗的替代方法。我们正在为50岁的绝经后妇女推荐ER2特异性植物serm组合作为第一个人体研究的I至IIa期试点开发项目。I期桥接研究在连续3组9名参与者中使用递增剂量来评估耐受性、药代动力学和4周暴露的潜在安全性。IIa期概念验证，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。鉴于大豆异黄酮提取物可作为膳食补充剂，并且该化合物“通常被认为是安全的”（GRAS，根据FDA法规），我们预计这种植物serm组合的耐受性非常好，并且在12周内不会发生不良事件。由于作为膳食补充剂销售的大豆衍生异黄酮没有经过正式的药物开发，而且这是一种新的植物serm组合，我们相信，对植物serm的谨慎，逐步开发方法将提供系统的信息，更好地受益于临床知识，并为未来的开发提供平台。

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.