Minocycline to Improve Neurologic Outcome (MINO Clinical Trial)

描述（由申请人提供）：米诺环素是一种安全且耐受性良好的抗生素，具有良好的血脑屏障穿透性。最近的证据表明二甲胺四环素是一种很有前途的神经保护剂，在动物模型的全域和局灶性缺血中有效。二甲胺四环素具有抗炎和抗凋亡作用，并抑制基质金属蛋白酶。此外，二甲胺四环素在啮齿类动物暂时性局灶性缺血模型中具有神经保护作用，其血清浓度可能在人类中实现。米诺环素目前在帕金森病、肌萎缩侧索硬化症、亨廷顿病和多发性硬化症的临床试验中。该建议是米诺环素治疗急性缺血性卒中的Ib/lla期临床试验。该研究的中心假设是，在动物模型中，当以与神经保护相关的剂量、途径和时间窗口给药时，二甲胺四环素在急性缺血性卒中患者中是安全且耐受的。我们计划通过使用开放标签、非随机、剂量递增设计进行剂量发现研究，并采用一种新颖的卒中试验统计方法，即改进的持续再评估方法，来检验我们的中心假设并实现本申请的总体目标。具体目标是：1)确定急性缺血性卒中患者静脉注射米诺环素的最大耐受剂量（MTD）。2)。二甲胺四环素在缺血性脑卒中患者体内的药动学研究测定不同剂量米诺环素对血浆MMP-9活性的影响收集不同剂量米诺环素对功能结局影响的初步数据。该建议将为米诺环素治疗急性缺血性卒中的后期ii / ii期研究提供关键数据。目前迫切需要一种安全有效的神经保护剂，可以用于不同的中风患者群体。由于二甲胺四环素是一种安全的药物，而且可能对脑出血也有作用，因此它极有可能成为一种“野战药物”，由救护人员和农村医院给药。

DESCRIPTION (provided by applicant): Minocycline is a safe and well-tolerated antibiotic with excellent blood-brain barrier penetration. Recent evidence demonstrates that minocycline is a promising neuroprotective agent and is effective in animal models of global and focal ischemia. Minocycline has anti-inflammatory and anti-apoptotic effects and also inhibits the matrix metalloproteinases. Moreover, minocycline is neuroprotective in a rodent model of temporary focal ischemia at serum concentrations that are likely to be achievable in humans. Minocycline is presently in clinical trial in Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and multiple sclerosis. This proposal is a phase Ib/lla clinical trial of minocycline in acute ischemic stroke. The central hypothesis is that minocycline will be safe and tolerable in acute ischemic stroke patients when administered in a dose, route, and time window associated with neuroprotection in animal models. We plan to test our central hypothesis and accomplish the overall objective of this application by performing a dose-finding study using an open label, non-randomized, dose escalation design with a novel statistical method for stroke trials, the modified continual reassessment method. The specific aims are: 1.) Determine the maximally tolerated dose (MTD) of intravenous minocycline in patients with acute ischemic stroke. 2.) Determine the pharmacokinetics of minocycline in patients with ischemic stroke 3.) Determine the effect of different doses of minocycline on plasma MMP-9 activity 4.) Gather preliminary data of the effect of different doses of minocycline on functional outcome This proposal will generate data that is critical to the development of a later phase ll/lll study of minocycline in acute ischemic stroke. There is a desperate need for a safe and effective neuroprotective agent that could be given to a diverse group of stroke patients. Since it is a safe drug and may also have activity against intracerebral hemorrhage, minocycline has excellent potential to become a "field drug", administered by ambulance crews and in rural hospitals.