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渗透性。最近的证据表明，米诺环素是一种有前途的神经保护剂，是有效的动物模型的全球和局灶性缺血。米诺环素具有抗炎和抗凋亡作用，并抑制基质金属蛋白酶。此外，米诺环素在啮齿动物模型的暂时性局灶性缺血中具有神经保护作用，其血清浓度可能在人类中达到。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。本提案是米诺环素治疗急性缺血性卒中的Ib/IIa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可耐受的。我们计划通过使用开放标签、非随机、剂量递增设计和卒中试验的新型统计方法（改良的持续再评估方法）进行剂量探索研究，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.）的情况。确定米诺环素在缺血性卒中患者中的药代动力学3.）测定不同剂量米诺环素对血浆MMP-9活性的影响4.）收集不同剂量米诺环素对功能结果影响的初步数据该提议将产生对米诺环素在急性缺血性卒中中的II/III期研究的后期发展至关重要的数据。迫切需要一种安全有效的神经保护剂，可以用于各种中风患者。由于米诺环素是一种安全的药物，也可能对脑出血有活性，因此它具有成为救护人员和农村医院使用的“战地药物”的极好潜力。

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.