Novel Treatment of menopausal hot flushes with an extradiol prodrug

用额外二醇前药治疗更年期潮热的新方法

基本信息

批准号：
7657235
负责人：
ISTVAN Jozsef MERCHENTHALER
金额：
$ 40.55万
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：
2009-03-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7657235
关键词：
Acute Address Adverse effects Affect Aftercare Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Andropause Animal Model Animals Anterior Pituitary Gland Antioxidants Anxiety Appearance Area Attenuated 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 Clinical Clonidine Complement 3 Conjugated Estrogens Data Development Dose Drops Drug Kinetics Drug or chemical Tissue Distribution Endometrial Enzymes Epithelial Epithelial Cells Estradiol Estrogen Receptors Estrogen Replacement Therapy Estrogen Replacements Estrogens Estrone Event Face Fatigue Female Flushing Gene Expression Genes Genetic Polymorphism Goals Gold Heart Heating Hemorrhage Hormone replacement therapy Hormones Hot flushes Human Hydroquinones Hydroxyl Radical Hypertrophy Hypothalamic structure In Vitro Knock-out Knockout Mice 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 Oral Administration Organ Ovariectomy Ovary Palpitations Parents Perimenopause Periodicity Pharmaceutical Preparations Phase Physiologic Thermoregulation Pituitary Gland Placebo Effect Plasma Play Postmenopause Prodrugs Progesterone Receptors Progestin Therapy Progestins Public Health Quality of life Rattus Reaction Receptor Gene Reporting Research Risk Risk Factors Role Series Serotonin Serum Skin Skin Temperature Sleep disturbances Spottings Sweat Sweating Sympathetic Nervous System Symptoms Tail Testing Tissues Tumor Volume United States Upper arm Uterus Vasodilation Weight Withdrawal Woman Work Xenograft procedure absorption base bone brain tissue cigarette smoking depression design drug discovery effective therapy experience improved in vivo in vivo Model inhibitor/antagonist innovation malignant breast neoplasm medical attention men middle age mouse model neoplastic cell novel novel strategies prevent public health relevance research study reuptake subcutaneous 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 sleep disturbances resulting in fatigue, depression, irritability, and forgetfulness, as well as acute physical discomfort and negative effects on work. Current therapies include estrogen or hormone (estrogens + progestins) therapies (ERT and HRT), clonidine, the selective serotonin and/or norepinephrine reuptake inhibitors, and gabapentine. Although ERT or HRT is efficacious in preventing hot flushes, a large number of women cannot or do not want to take estrogen. The efficacy of the other therapies is questionable. Therefore, there is a huge unmet need for a better and safer ERT or HRT. We propose in this application that para-quinol of 17b-estradiol (Q-E1) has the potential to be considered as the optimal ERT. We have shown earlier that para-quinol of estrone (Q-E1) functions as a pro-drug and following its absorption its is converted in selective tissues to E1 via an enzyme catalyzed mechanism involving NADP(H). This conversion is effective in the brain but not in the uterus, breast, or the pituitary gland. Therefore, treatment with quinols of estrogens do not have uterotropic (spotting, bleeding, cancer) and mammotropic (breast cancer) liabilities like any other estrogens, including the frequently used Premarin. 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, primarily hot flushes. Our pilot data strongly indicate that Q-E2 blocks hot flush symptoms in a rat model of hot flush, 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 hot flushes. The proposal describes a series of studies aimed at (i) dissecting out the dynamics of Q-E2/E2 conversion in brain areas involved in thermoregulation, (ii) establishing the optimal dose of Q-E2 following its subcutaneous and oral administration using two rat models of hot flush, (iii) provide evidence that the beneficial actions of Q-E2 are mediated via estrogen receptors, and (iv) confirm the lack of action in the uterus and breast, and the beneficial effects in the bone following its chronic administration to ovariectomized rats. 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 has not been tested experimentally, Q-E2 might be the choice of therapy of men in the andropause as well. In addition, the pro-drug approach we propose here could provide an impetus for drug discovery of other related or un-related therapies. PUBLIC HEALTH RELEVANCE: Peri-menopausal hot flushes pose a significant public health concern world-wide. Although hormone replacement therapy, alleviates hot flushes in the majority of women, a large number of peri-menopausal women cannot take or do not want to take hormones. Therefore, there is still 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, i.e., the use of para-quinol of estrogen as a prodrug approach. The prodrug is converted to estrogen in brain but not uterus and breast, and as a result, it blunts hot flushes in an animal model of hot flush.

描述（由申请人提供）：热潮在全球范围内引起了重大公共健康问题。这些上绝经症状是妇女在更年期过渡期间寻求医疗护理的主要原因。热潮通常会对女性的生活质量产生负面影响，因为它们与睡眠障碍有关，导致疲劳，抑郁，烦躁和健忘，以及对工作的急性身体不适和负面影响。当前的疗法包括雌激素或激素（雌激素 +孕激素）疗法（ERT和HRT），可乐定，选择性5-羟色胺和/或去甲肾上腺素再摄取抑制剂和加巴喷丁。尽管ERT或HRT有效防止潮热，但许多女性不能或不想服用雌激素。其他疗法的功效值得怀疑。因此，巨大的未满足需要更好，更安全的ERT或HRT。我们在此应用中提出，17b-雌二醇（Q-E1）的二醇具有被视为最佳ERT的潜力。我们之前已经证明，雌酮（Q-E1）的二醇作为pro-prug起作用，并在其吸收后通过涉及NADP（H）的酶催化的机制将其在选择性组织中转化为E1。这种转化在大脑中有效，但在子宫，乳腺或垂体中不有效。因此，用雌激素的喹诺醇治疗没有子宫核（斑点，出血，癌症）和乳腺癌（乳腺癌）责任，例如任何其他雌激素，包括常用的前菜蛋白。由于E2是人类卵巢产生的主要，最有效的雌激素，因此我们建议将Q-E2视为治疗临时症状症状的亲药，主要是热潮。我们的飞行员数据强烈表明，Q-E2会阻止大鼠热冲洗模型中的热冲洗症状，但不会刺激MCF-7乳腺细胞或子宫的增殖，或者以阻断热冲洗症状的剂量。因此，Q-E2似乎是一种新颖，安全和最佳的ERT，可减轻围绝经层的冲洗。该提案描述了一系列研究，旨在（i）解剖涉及体温调节涉及的大脑区域的Q-E2/E2转化的动态，（ii）在其皮下和口服后使用两种大鼠使用HOD FLUSH模型（III）的最佳剂量Q-E2的最佳剂量，（III）提供了Q-E2的有益动作的证据，并介导了Q-e2的作用。和乳房，以及长期给予卵巢切除大鼠后骨骼的有益作用。发现新颖且安全的ERT将改善全球范围内数亿次围绝经苏联妇女的生活质量，因此，将对公共卫生产生巨大影响。尽管尚未通过实验进行测试，但Q-E2也可能是男性在Andropause中的选择。此外，我们在这里提出的亲毒品方法可能会为药物发现其他相关或无关的疗法提供动力。公共卫生相关性：绝经周围的热冲洗在全球范围内引起了一个重大的公共卫生问题。尽管激素替代疗法减轻了大多数女性的热潮，但大量的绝经妇女不能服用或不想服用激素。因此，对于更年期症状的更好，更安全的疗法仍然存在巨大的需求。该提案通过研究潜在的无负债雌激素替代疗法来解决这种未满足的需求，即使用雌激素的para- Quinol作为前药方法。该前药在大脑中转化为雌激素，而不是子宫和乳房，因此，它在热潮的动物模型中钝化了热冲洗。