Combination progesterone & vitamin D in treatment of Traumatic Brain Injury

描述(申请人提供)：数十项创伤性脑损伤(TBI)治疗的II期和III期临床试验均失败。其中提到的一个原因是，作用模式有限的药物没有解决与不同类型的创伤性脑损伤相关的复杂机制和损伤级联反应。孕酮(PROG)已被证明是治疗脑外伤的一种安全有效的方法。使用PROG治疗中重度脑损伤的I/II期临床试验发现，重度损伤的死亡率降低了近60%，功能结果更好。这项试验在另一项来自国外的独立研究中与另外159名患者进行了重复。PIs目前的研究正在通过将Prog与其他神经保护剂结合起来寻求更好的结果。合乎逻辑的第一步是检查在临床环境中可能限制PROG有益效果的条件。维生素D激素是FDA批准的一种分子，其神经保护和神经营养作用日益得到认可。PIs最近的研究表明，对于年长的受试者，Vdh缺乏(VDHdef)会减少Prog的有益影响。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脑外伤的结局，而老年人口更容易受到脑外伤的影响。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，如果同时存在VDH缺陷，则可能面临更高的风险，并产生较差的预后。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好处。Prog和Vdh都是自然荷尔蒙，在男性和女性中都会合成，在中枢神经系统修复中具有不同的、多效性的作用模式。这些特性使联合使用PROG和VDH的临床前试验成为值得考虑的方法，以供以后在临床TBI试验中进行评估和测试。首先，PIs将确定联合治疗的最佳剂量，以增强PROG在创伤后从神经缺陷中恢复的效果，并解决雄性和雌性大鼠的病变大小。其次，他们将观察在老年动物中，Prog的效果是否在Vdh缺乏的共病状态下受到影响，以及是否有必要补充Vdh来促进最佳益处。第三，如果有的话，他们将在Prog和VIH水平、功能恢复和替代血清生物标记物的血清水平之间建立联系。为了测量损伤的严重程度和预测修复程度，将评估神经预后和血清TBI标志物水平变化的时间进程。第四，PI将通过结合PROG和VDH来确定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使用任何一种药物后变化最显著的基因产物，以及与大脑损伤和修复最相关的基因产物。 公共卫生相关性：孕酮(PROG)已被证明是治疗中重度创伤性脑损伤的一种安全有效的治疗方法。有证据表明，将其与维生素D激素(VDH)联合使用可以提高其有效性，特别是在老年人中。事实上，PROG和VDH都有很高的安全性，对许多不同的损伤和病理机制起作用，而且易于管理和价格低廉，这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途径。

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.