Progesterone in the Treatment of ischemic Stroke

描述(由申请人提供)：到目前为止，治疗缺血性中风的临床试验一直令人失望。然而，在最近完成的一项针对中重度创伤性脑损伤(TBI)患者的11a期单中心随机双盲试验中，与接受最先进治疗和安慰剂的患者相比，伤后3天静脉注射黄体酮(PROG)可将死亡率降低近60%，并显著改善存活30天的功能结果。PROG在卒中治疗中的初步数据是有希望的，但在PROG可以在卒中的临床试验中测试之前，需要更多的动物研究来确定卒中和脑外伤之间的剂量反应关系和治疗机会窗口是否不同。我们将确定PROG的安全性、给药参数以及对目标动物类别的生理和功能结果的影响。然后，我们将申请并获得FDA的批准，将PROG用于治疗缺血性中风的临床试验。在目前的提案中，我们将在雌性和雄性大鼠中使用短暂性和永久性脑缺血中风模型。我们的主要目标将是确定PROG是否在“中年”雄性和雌性大鼠(大约15个月)中有效，这是中年人群比年轻大鼠更容易患中风的更好的模型。其次，我们将与三个以动物中风研究闻名的实验室合作，在大鼠身上建立随机、双盲的“多实验室试验”模型。第三，我们将检查损伤和治疗后的长期功能结果，看看PROG的影响是否持久。第四，我们将把我们的治疗参数扩展到容易中风的大鼠，这样我们的中风模型就更具人类风险因素的特征。第五，我们将使用这些数据向FDA申请IND来测试人类中风患者的PROG。我们相信，U01的翻译研究合作协议是我们的实验室和我们的合作者提供所需的翻译数据的理想方式，可以将PROG作为中风的治疗方法进行临床测试。 相关性：中风仍然是世界范围内的一个主要公共卫生问题。除了tPA，在研究的700多种药物中，没有一种在临床试验中被证明有效。Prog已被证明在临床脑外伤中安全有效，我们现在需要确定它在缺血性卒中的临床治疗中是否同样有效。这里提出的研究让我们更接近这种可能性。

DESCRIPTION (provided by applicant): To date, clinical trials for the treatment of ischemic stroke after it has occurred have been disappointing. However, in a recently completed Phase lla, single-center, randomized, double-blind trial in patients with moderate to severe traumatic brain injury (TBI), progesterone (PROG), given intravenously for three days after injury, reduced mortality by almost 60% and significantly improved functional outcome at 30 days survival compared to patients given state-of-the-art treatment and placebo. Preliminary data with PROG in the treatment of stroke are promising, but before PROG can be tested in a clinical trial for stroke, more animal studies are needed to determine whether dose response relationships and window of treatment opportunity differ between stroke and TBI. We will establish the safety, dosing parameters, and effects on physiological and functional outcomes of PROG in the target class of animal subjects. We will then apply for, and gain, FDA approval to use PROG in a clinical trial for the treatment of ischemic stroke. In the present proposal we will use both transient and permanent cerebral ischemic stroke models in both female and male rats. Our Primary goal will be to determine whether PROG will work effectively in "middle-aged" male and female rats (about 15 months), which are better models of the middle-aged population more at risk for stroke than younger counterparts. Second, we will collaborate with three laboratories known for their animal stroke research to model a randomized, double-blind "multi-laboratory trial" in rats. Third, we will examine long- term functional outcomes after the injury and treatment to see whether PROG's effects are enduring. Fourth, we will extend our treatment parameters to stroke-prone rats, so our stroke models are more characteristic of the risk factors seen in humans. Fifth, we will use these data to apply to the FDA for an IND to test PROG in human stroke patients. We believe the U01 cooperative agreement for translational research is an ideal way for our laboratory and those of our collaborators to provide the translational data needed to move to clinical testing of PROG as a treatment for stroke. RELEVANCE: Stroke remains a major public health problem worldwide. Aside from tPA, of the more than 700 drugs studied, none have proven effective in clinical trial. PROG has been shown to be safe and effective in clinical TBI and we now need to determine whether it can be as effective in the clinical treatment of ischemic stroke. The studies proposed here move us closer to that possibility.