Combination progesterone & vitamin D in the treatment of Traumatic Brain Injury

描述（由申请人提供）：数十项创伤性脑损伤（TBI）治疗的II期和III期临床试验失败。其中一个原因是，与不同类型的TBI相关的复杂机制和损伤级联反应并没有被作用模式有限的药物所解决。孕酮（PROG）已被证明是一种安全有效的治疗创伤性脑损伤的方法。一项使用PROG治疗中重度脑损伤的I/II期临床试验发现，重度脑损伤的死亡率降低了近60%，并且功能预后更好。该试验在另一项来自国外的独立研究中复制了159名患者。pi目前的研究是通过将PROG与其他神经保护剂结合使用来寻求更好的结果。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作用的条件。维生素D激素（VDH）是fda批准的一种具有神经保护和神经营养作用的分子。pi最近的研究表明，对于老年受试者，VDH缺乏（VDHdef）会降低PROG的有益作用。据报道，超过一半的老年人是VDHdef，这种情况可能加剧任何创伤性脑损伤的结果，老年人不成比例地受到创伤性脑损伤的影响。此外，据报道，约有30-35%的美国公众患有VDHdef，因此，任何年龄的患者，包括儿童，如果他们也缺乏VDH，则表现为TBI的风险更大，预后也更差。因此，像VDH这样简单的东西可以增强PROG治疗作为神经保护剂的益处。PROG和VDH都是天然激素，在男性和女性中都可以合成，并且在中枢神经系统修复中具有不同的多效性作用模式。这些特性使得联合PROG和VDH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试验中进行后期评估和测试。首先，pi将确定联合治疗的最佳剂量，以增强PROG对雄性和雌性大鼠创伤后神经功能缺损恢复和病变大小消退的作用。其次，他们将观察PROG的作用是否在老年动物的共病VDH缺乏状态下受到损害，以及是否有必要补充VDH以促进最佳效益。第三，他们将建立PROG和VDH水平、功能恢复和TBI替代血清生物标志物血清水平之间的相关性。为了测量损伤的严重程度和预测修复的程度，将评估神经预后和TBI标志物血清水平变化的时间过程。第四，pi将确定PROG与VDH联合使用有助于更好地保护神经的机制。pi将分析在联合治疗或单独用药中变化最显著的基因产物，以及与脑损伤和修复最相关的基因产物。

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.