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Combination progesterone & vitamin D in treatment of Traumatic Brain Injury

组合黄体酮

基本信息

批准号：
8300152
负责人：
DONALD G. STEIN
金额：
$ 28.27万
依托单位：
EMORY UNIVERSITY
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：
2009-07-15 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8300152
关键词：
3 year old Acute Address Adverse effects Affect Age American Animals Antioxidants Apoptosis Basic Science Behavior Behavioral Biological Markers Brain Brain Injuries Calcitriol Cerebral Edema Cessation of life Child China Clinical Clinical Data Clinical Trials Combined Modality Therapy Companions Complement Complex Cortical Contusions Cytokine Receptors Data Dose Effectiveness Elderly Event FDA approved Failure Female Funding Gene Expression Genes Genetic Transcription Health Heterogeneity Hormones Human In Situ Individual Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Laboratories Laboratory Animals Lead Lesion Measures Metabolic Modeling Molecular Necrosis Neuraxis Neurologic Neurological outcome Neuron-Specific Enolase Neurons Neuroprotective Agents Operative Surgical Procedures Outcome Oxidative Stress Pathway interactions Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase II Clinical Trials Phase III Clinical Trials Physiological Population Preclinical Testing Process Prodrugs Progesterone Property Proteins Rattus Recovery Recovery of Function Regulation Reporting Request for Applications Research Research Personnel Resolution Risk S100 Proteins Safety Scientist Serum Severities Sex Characteristics Staging Supplementation Surrogate Markers Testing Time Tissues Traumatic Brain Injury Treatment Efficacy Universities Vitamin D Work aged body system brain repair brain tissue clinically relevant combinatorial cytokine cytotoxicity effective therapy evaluation/testing functional outcomes hormone deficiency improved injured injury and repair male mitochondrial dysfunction mortality neurological recovery neuroprotection neurosteroids neurotrophic factor pre-clinical protein expression repaired research study response senescence treatment effect young adult

项目摘要

DESCRIPTION (provided by applicant): Dozens of phase II and III clinical trials for traumatic brain injury (TBI) therapies have failed. One reason cited is that the complex mechanisms and injury cascades associated with different types of TBI are not being addressed by drugs with limited modes of action. Progesterone (PROG) has been shown to be a safe and effective treatment for TBI. A phase I/II clinical trial using PROG to treat moderate to severe brain injury found that mortality from severe injury was reduced almost 60% and there was better functional outcome. This trial was replicated with an additional 159 patients in an independent study from abroad. The PIs' current research is seeking even better results by combining PROG with other neuroprotective agents. A logical first step is to examine the conditions that might limit PROG's beneficial effects in a clinical setting. Vitamin D hormone (VDH) is an FDA-approved molecule whose neuroprotective and neurotrophic actions are increasingly being recognized. The PIs' recent research suggests that, for older subjects, VDH deficiency (VDHdef) reduces the beneficial effects of PROG. It has been reported that well over half of older adults are VDHdef, a condition which could exacerbate the outcome of any TBI, and the elderly population is disproportionately subject to TBI. Further, about 30-35% of the American public has been reported to be VDHdef, so patients of any age, including children, presenting with a TBI could be more at risk and have less favorable outcome if they are also VDH deficient. Thus something as simple as VDH could enhance the benefit of PROG treatment as a neuroprotective agent. Both PROG and VDH are natural hormones, synthesized in both males and females, and have distinct, pleiotropic modes of action in CNS repair. These properties make the preclinical testing of combined PROG and VDH a compelling approach to consider for later evaluation and testing in a clinical TBI trial. First, the PIs will determine the optimal dose for combination treatment to enhance PROG's effects on post- traumatic recovery from neurological deficits and resolution of lesion size in male and female rats. Second, they will see whether PROG's effects are compromised in a co-morbid VDH deficient state in old animals and whether supplementing VDH is necessary to promote optimal benefit. Third, they will establish a correlation, if any, between PROG and VDH levels, functional recovery, and serum levels of surrogate serum biomarkers for TBI. To measure the severity of the injury and predict extent of repair, the time course of changes in neurologic outcome and serum levels of TBI markers will be evaluated. Fourth, the PIs will identify mechanisms that contribute to better neuroprotection by combination of PROG with VDH. The PIs will analyze the gene products most significantly changed in response to combination treatment or either agent alone, and most related to brain injury and repair. PUBLIC HEALTH RELEVANCE: Progesterone (PROG) has been shown to be a safe and effective treatment for moderate and severe traumatic brain Injury. There is evidence that its effectiveness can be increased by combining it with Vitamin D hormone (VDH), especially in the elderly. The fact that both PROG and VDH have high safety profiles, act on many different injury and pathological mechanisms, and are easy to administer and inexpensive, make this combination an obvious approach to develop what may become the first successful treatment for traumatic brain injury.

描述（由申请人提供）：数十项针对创伤性脑损伤（TBI）治疗的 II 期和 III 期临床试验均已失败。引用的原因之一是，与不同类型 TBI 相关的复杂机制和损伤级联并未通过作用方式有限的药物来解决。黄体酮 (PROG) 已被证明是一种安全有效的 TBI 治疗方法。一项使用 PROG 治疗中度至重度脑损伤的 I/II 期临床试验发现，重度损伤的死亡率降低了近 60%，并且具有更好的功能结果。这项试验在国外的一项独立研究中又对另外 159 名患者进行了重复。 PI 目前的研究正在寻求通过将 PROG 与其他神经保护剂结合起来获得更好的结果。合乎逻辑的第一步是检查可能限制 PROG 在临床环境中的有益效果的条件。维生素 D 激素 (VDH) 是 FDA 批准的一种分子，其神经保护和神经营养作用越来越受到认可。 PI 最近的研究表明，对于老年受试者，VDH 缺乏 (VDHdef) 会降低 PROG 的有益效果。据报道，超过一半的老年人患有 VDHdef，这种情况可能会加剧任何 TBI 的后果，而且老年人口中遭受 TBI 的比例不成比例。此外，据报道，大约 30-35% 的美国公众患有 VDHdef，因此，任何年龄的患者（包括儿童）如果也缺乏 VDH，则出现 TBI 的风险可能更大，并且预后较差。因此，像 VDH 这样简单的东西就可以增强 PROG 作为神经保护剂的治疗效果。 PROG 和 VDH 都是天然激素，在男性和女性中均合成，并且在中枢神经系统修复中具有独特的多效性作用模式。这些特性使得 PROG 和 VDH 组合的临床前测试成为一种令人信服的方法，可以考虑在临床 TBI 试验中进行后续评估和测试。首先，PI 将确定联合治疗的最佳剂量，以增强 PROG 对雄性和雌性大鼠的创伤后神经缺陷恢复和病变大小消退的作用。其次，他们将了解在老年动物同时患有 VDH 缺乏的情况下，PROG 的效果是否会受到损害，以及是否有必要补充 VDH 以促进最佳效果。第三，他们将在 PROG 和 VDH 水平、功能恢复以及 TBI 替代血清生物标志物的血清水平之间建立相关性（如果有的话）。为了测量损伤的严重程度并预测修复程度，将评估神经系统结果变化的时间过程和 TBI 标记物的血清水平。第四，PI 将确定通过 PROG 与 VDH 组合有助于更好的神经保护的机制。 PI 将分析联合治疗或单独使用任一药物后发生最显着变化的基因产物，并且与脑损伤和修复最相关。公共卫生相关性：黄体酮 (PROG) 已被证明是治疗中度和重度脑外伤的安全有效的方法。有证据表明，将其与维生素 D 激素 (VDH) 结合使用可以提高其有效性，尤其是对于老年人。事实上，PROG 和 VDH 都具有很高的安全性，可作用于许多不同的损伤和病理机制，并且易于管理且价格低廉，使得这种组合成为开发可能成为第一个成功治疗创伤性脑损伤的方法的明显方法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progesterone is neuroprotective against ischemic brain injury through its effects on the phosphoinositide 3-kinase/protein kinase B signaling pathway.

DOI：
10.1016/j.neuroscience.2012.03.008
发表时间：
2012-05-17
期刊：
Neuroscience
影响因子：
3.3
作者：
Ishrat T;Sayeed I;Atif F;Hua F;Stein DG
通讯作者：
Stein DG

The TRIF-dependent signaling pathway is not required for acute cerebral ischemia/reperfusion injury in mice.

DOI：
10.1016/j.bbrc.2009.10.027
发表时间：
2009-12-18
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Hua, Fang;Wang, Jun;Sayeed, Iqbal;Ishrat, Tauheed;Atif, Fahim;Stein, Donald G.
通讯作者：
Stein, Donald G.

Progesterone and vitamin D: Improvement after traumatic brain injury in middle-aged rats.

DOI：
10.1016/j.yhbeh.2013.06.009
发表时间：
2013-08
期刊：
HORMONES AND BEHAVIOR
影响因子：
3.5
作者：
Tang, Huiling;Hua, Fang;Wang, Jun;Sayeed, Iqbal;Wang, Xiaojing;Chen, Zhengjia;Yousuf, Seema;Atif, Fahim;Stein, Donald G.
通讯作者：
Stein, Donald G.

Progesterone and allopregnanolone attenuate blood-brain barrier dysfunction following permanent focal ischemia by regulating the expression of matrix metalloproteinases.