Novel Treatment of Menopausal Hot Flushes with an Extradiol Prodrug

用 Extradiol 前药治疗更年期潮热的新方法

基本信息

批准号：
7811694
负责人：
ISTVAN Jozsef MERCHENTHALER
金额：
$ 70.55万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2012-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7811694
关键词：
Acute Address Adverse effects Affect Aftercare Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Andropause Animal Model Animals Anterior Pituitary Gland Antidepressive Agents Antioxidants Anxiety Appearance Area Attenuated Behavior Behavioral Behavioral Model Biological Biological Availability Body Temperature Brain Brain region Breast Breast Cancer Cell CYP1B1 gene Cancer cell line Caring Cell Proliferation Cells Central Nervous System Diseases Chills Chronic Cigarette Clinical Clonidine Complement 3 Data Development Disease Dose Drops Drug Kinetics Drug or chemical Tissue Distribution Endometrial Enzymes Epithelial Epithelial Cells Estradiol Estrogen Receptor alpha Estrogen Receptor beta Estrogen Receptors Estrogen Replacement Therapy Estrogen Replacements Estrogens Estrone Event Face Fatigue Female Flushing Foundations Frequencies Funding Gene Expression Genes Genetic Polymorphism Goals Gold Grant Heart Heating Hormone replacement therapy Hormones Hot flushes Human Hydroquinones Hydroxyl Radical Hypertrophy Hypothalamic structure Hysterectomy In Vitro Knock-out Knockout Mice Laboratories Life Liver MCF7 cell Malignant Neoplasms Mammary Gland Parenchyma Mammary Neoplasms Measurement Measures Mediating Medical Menopausal Symptom Menopause Microscopic Modeling Morphine Mus Naloxone Natural regeneration Neuraxis Neurons Norepinephrine Obesity Oral Organ Ovariectomy Ovary Palpitations Parents Parkinson Disease Pathogenesis Pattern Perimenopause Periodicity Peripheral Pharmaceutical Preparations Phase Physiologic Thermoregulation Pituitary Gland Placebo Effect Plasma Play Polysomnography Postmenopause Prodrugs Progesterone Progesterone Receptors Progestins Psychiatric therapeutic procedure Puberty Public Health Quality of life Rattus Reaction Receptor Gene Reporting Research Risk Risk Factors Rodent Model Role Series Serotonin Serum Severities Skin Skin Temperature Sleep Sleep Architecture Sleep Disorders Sleep Stages Sleep disturbances Smoke Stress Sweat Sweating Swimming Sympathetic Nervous System Symptoms Tail Tail Suspension Testing Time Tissues Tumor Volume United States Upper arm Uterus Vasodilation Weight Withdrawal Woman Work Xenograft procedure absorption base behavior change brain tissue depression depressive symptoms design effective therapy experience improved in vivo in vivo Model inhibitor/antagonist innovation medical attention men middle age mouse model neoplastic cell novel novel strategies parent grant prevent public health relevance research study reuptake sleep onset tissue culture

项目摘要

DESCRIPTION (provided by applicant): Hot flushes pose a significant public health concern world-wide. These perimenopausal symptoms are the primary reason that women seek medical care during the menopausal transition. Hot flushes often negatively impact the quality of life of women because they are associated with anxiety/depression and sleep disturbances resulting in fatigue, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work. Although estrogen replacement therapy (ERT) is efficacious in preventing hot flushes, a large number of women cannot or do not want to take estrogen, and the peripheral side-effects are potentially life threatening. The efficacy of the other therapies is questionable. Therefore, there is a huge unmet need for a better and safer ERT We propose in this application that para-quinol of 17b-estradiol (Q-E2) has the potential to be considered as the optimal ERT. We have shown earlier that Q-E2 functions as a pro-drug and following its absorption it is converted in selective tissues to E2 via an enzyme catalyzed mechanism. This conversion is effective in the brain but not in the uterus, breast, or the pituitary gland. Therefore, treatment with Q-E2 would not have uterotropic and mammotropic liabilities like any other estrogens. Since E2 is the primary and most potent estrogen produced by the human ovary, we propose to consider Q-E2 as a pro-drug for the treatment of perimenopausal symptoms including not only hot flushes as we proposed in the parent grant but anxiety/depression and altered sleep pattern by utilizing animal models of these menopausal disturbances. Our pilot data strongly indicate that Q-E2 blocks hot flush symptoms in a rat model of hot flush, reduces depression in the forced swim test model of behavioral despair, but does not stimulate proliferation in MCF-7 breast cells or the uterus at doses that block the hot flush symptoms. Therefore, Q-E2 seems to be a novel, safe, and optimal ERT for alleviating perimenopausal symptoms, including hot flushes, anxiety/depression and sleep disturbances. The supplement describes a series of experiments aimed at evaluating the effect of orally-administered Q-E2 in (i) rat and mouse models of anxiety/depression and (ii) rat and mouse models of estrogen-regulated sleep patterns. Since the development of estrogen receptor-alpha (ERa)- or estrogen receptor-beta (ERb)-selective pro-drugs are being developed in our laboratories, the experiments will also involve (ERa)-knockout and (ERb)- knockout mice to determine the ER responsible for any effects of Q-E2. The discovery of a novel and safe ERT would improve the quality of life of hundreds of millions of perimenopausal women world-wide and thus, would have a tremendous impact on public health. Although it has not been tested experimentally, Q-E2 might be a choice for psychiatric therapy of men in the andropause as well. PUBLIC HEALTH RELEVANCE: Peri-menopausal symptoms, such as hot flushes, anxiety/depression, and sleep disturbances pose a significant public health concern world-wide. Although hormone replacement therapy, alleviates hot flushes and ease anxiety/depression and improve sleep in the majority of women, a large number of peri-menopausal women cannot take or do not want to take hormones because of their side effects. Therefore, there is a huge unmet need for better and safer therapies for menopausal symptoms. The proposal addresses this unmet need by investigating a potentially liability-free estrogen replacement therapy (ERT) utilizing animal models of hot flush, anxiety/depression, and sleep pattern. Para-quinol of estrogen (pro-drug) is converted to estrogen in brain but not in uterus and breast, and therefore, provides the foundation to develop a novel and safe, central nervous system-selective ERT.

描述（由申请人提供）：潮热在全世界范围内构成了重大的公共卫生问题。这些围绝经期症状是女性在更年期过渡期间寻求医疗护理的主要原因。潮热通常会对女性的生活质量产生负面影响，因为它们与焦虑/抑郁和睡眠障碍有关，导致疲劳、易怒和健忘，以及严重的身体不适和对工作的负面影响。尽管雌激素替代疗法（ERT）可有效预防潮热，但大量女性不能或不想服用雌激素，而且其外周副作用可能危及生命。其他疗法的疗效值得怀疑。因此，对于更好、更安全的 ERT 存在巨大的未满足需求。我们在此申请中提出，17b-雌二醇的对羟基苯酚 (Q-E2) 有可能被视为最佳 ERT。我们之前已经证明，Q-E2 作为前药发挥作用，吸收后，它通过酶催化机制在选择性组织中转化为 E2。这种转换在大脑中有效，但在子宫、乳房或垂体中无效。因此，使用 Q-E2 治疗不会像任何其他雌激素那样具有促子宫和促乳腺作用。由于 E2 是人类卵巢产生的主要且最有效的雌激素，因此我们建议将 Q-E2 视为治疗围绝经期症状的前药，这些症状不仅包括我们在家长资助中提出的潮热，还包括焦虑/抑郁和通过利用这些更年期障碍的动物模型改变睡眠模式。我们的试验数据强烈表明，Q-E2 可以阻断潮热大鼠模型中的潮热症状，减少行为绝望的强迫游泳测试模型中的抑郁，但在剂量为阻止潮热症状。因此，Q-E2 似乎是一种新颖、安全且最佳的 ERT，用于缓解围绝经期症状，包括潮热、焦虑/抑郁和睡眠障碍。该补充描述了一系列旨在评估口服 Q-E2 在 (i) 焦虑/抑郁大鼠和小鼠模型以及 (ii) 雌激素调节睡眠模式大鼠和小鼠模型中的效果的实验。由于我们的实验室正在开发雌激素受体-α（ERa）-或雌激素受体-β（ERb）-选择性前药，因此实验还将涉及（ERa）-敲除和（ERb）-敲除小鼠确定对 Q-E2 的任何影响负责的 ER。一种新颖且安全的 ERT 的发现将改善全世界数亿围绝经期妇女的生活质量，从而对公共健康产生巨大影响。尽管尚未经过实验测试，Q-E2 也可能成为男性更年期男性精神治疗的选择。公共卫生相关性：潮热、焦虑/抑郁和睡眠障碍等围绝经期症状在全世界范围内构成了重大的公共卫生问题。尽管激素替代疗法可以缓解大多数女性的潮热、缓解焦虑/抑郁并改善睡眠，但许多围绝经期女性由于激素的副作用而不能或不想服用激素。因此，对于更年期症状的更好、更安全的治疗方法存在巨大的未满足需求。该提案通过利用潮热、焦虑/抑郁和睡眠模式的动物模型研究一种潜在的无责任雌激素替代疗法（ERT）来解决这一未满足的需求。雌激素的对羟基苯酚（前药）在大脑中转化为雌激素，但不在子宫和乳房中转化为雌激素，因此，为开发新型安全的中枢神经系统选择性 ERT 奠定了基础。