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（ER 2）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的卵巢功能衰竭（绝经）。有一些合理的机制，通过这些机制，ER 2受体刺激可以改善认知，改善幸福感，降低认知障碍的风险，改善血管痉挛症状。 开发了一种由合理选择的ER 2选择性植物雌激素（phytoSERMs）组成的制剂，其提供比与ER 1和ER 2选择性组分混合的各种营养品更大的效果。这种新的配方是由合理定义的内容，诱导协同作用，而不是对雌激素受体的拮抗作用，并可能产生有益的治疗效果。该制剂通过向染料木黄酮和大豆苷元中加入雌马酚来增强ER 2应答，从而调节雌马酚产生中个体间差异的潜在影响。该制剂的三个主要潜在优势是：（1）减少在复杂的大豆衍生的抗肿瘤制剂中发生的拮抗相互作用;（2）最大限度地减少生殖组织中与ER 1激活相关的不良反应;（3）在ER 2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疗法的替代品。 我们正在为50岁范围内绝经后妇女的ER 2特异性phytoSERM组合提出I期至IIa期试点开发计划，作为首次人体研究。I期桥接研究在3个连续组（9名受试者）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期概念剂量范围验证、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。考虑到大豆提取物可作为膳食补充剂，并且这些化合物“通常被认为是安全的”（GRAS，根据FDA法规），我们预计这种植物SERM组合在12周内具有良好的耐受性和良性不良事件特征。由于作为膳食补充剂销售的大豆衍生的异黄酮不受正式药物开发的影响，并且这是一种新的植物SERM组合，我们相信，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。 公共卫生相关性：绝经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治疗。我们已经开发了一种植物雌激素分子的制剂，我们称之为PhytoSERM，其靶向雌激素受体β。这项研究将确定最佳剂量，安全性和耐受性的PhytoSERM在绝经后妇女经历潮热。我们还将进行试点分析，以确定PhytoSERMs显着减少潮热的功效。

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.