Minocycline to Improve Neurologic Outcome (MINO Clinical Trial)

说明(申请人提供)：米诺环素是一种安全、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，米诺环素是一种很有前途的神经保护剂，在全脑和局灶性脑缺血的动物模型中都是有效的。米诺环素具有抗炎、抗细胞凋亡的作用，对基质金属蛋白酶也有抑制作用。此外，米诺环素在暂时性局灶性脑缺血的啮齿动物模型中具有神经保护作用，其血清浓度很可能在人类身上也能达到。米诺环素目前正在帕金森氏病、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。本方案为米诺环素治疗急性缺血性卒中的Ib/11a期临床试验。中心假设是，米诺环素在动物模型中以与神经保护相关的剂量、途径和时间窗给药时，在急性缺血性卒中患者中是安全和耐受的。我们计划测试我们的中心假设，并通过使用开放标签、非随机、剂量递增设计和中风试验的新统计方法--改进的持续重新评估方法--进行剂量发现研究，来实现这一应用的总体目标。具体目标是：1.测定急性缺血性卒中患者静脉注射米诺环素的最大耐受量(MTD)。2.)测定米诺环素在缺血性卒中患者中的药代动力学。测定不同剂量米诺环素对血浆基质金属蛋白酶-9活性的影响。收集不同剂量的米诺环素对功能结果影响的初步数据这一建议将产生对米诺环素在急性缺血性卒中的后期研究中的发展至关重要的数据。人们迫切需要一种安全有效的神经保护剂，可以给不同类型的中风患者使用。由于米诺环素是一种安全的药物，而且可能具有抗脑出血的活性，因此它有很好的潜力成为由救护车工作人员和乡村医院使用的“野战药物”。

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.