ZZ-3K3A-201: Safety evaluation of 3K3A-APC in ischemic stroke

描述（由申请人提供）：中风是美国成年人残疾的主要原因，也是世界上主要的死亡原因之一。如果患者在中风开始后3小时内到达医院，溶栓治疗可能非常有效。然而，只有40%至50%的患者对溶解治疗有反应，因此优先开发新的有效的中风治疗方法。大脑由多种细胞类型组成：神经元，神经胶质细胞和内皮细胞等;在中风期间，大脑每分钟损失120万个神经元。在过去，未能使患者受益的候选中风治疗仅针对神经元。我们现在打算测试一种新的药物，它可以有效地保护神经元、神经胶质细胞和内皮细胞，这些细胞统称为神经血管单位。这种药物，3 K3 A-APC，部分通过PAR-1受体作用于细胞，通过多种机制诱导保护作用。多个实验室-在几个动物模型中使用神经行为和组织形态学终点-已经表明该药物可以有效降低实验性中风的影响，即使在中风开始后4小时内给药。在人类志愿者中，在临床相关剂量下仅检测到轻度和中度副作用。我们现在建议测试3 K3 A-APC-第一次-在中风患者谁到达医院非常早，并接受溶栓治疗。首先尝试非常低的剂量，然后逐渐尝试更高的剂量。最后，我们将确定最大耐受剂量（MTD），即在不引起严重副作用的情况下可以给予的最大药物剂量。在这项研究结束时，我们希望确定一个剂量，是安全的，并能很好地耐受急性中风患者。如果这项研究成功，下一步将是一项更大的研究，以测试3 K3 A-APC在中风患者中的可能益处。

DESCRIPTION (provided by applicant): Stroke is the leading cause of adult disability in America, and one of the leading causes of death in the world. If patients arrive at a hospital within 3 hours of their stroke beginning, thrombolytic therapy can be very effective. Only 40 to 50% of patients respond to lytic treatment, however, creating a priority to develop new, effective treatments for stroke. The brain consists of multiple cell types: neurons, glia, and endothelial cells, among others; during stroke, the brain loses 1.2 million neurons per minute. In the past, candidate stroke treatments that failed to benefit patients were targeted only at neurons. We now propose to test a new drug that powerfully protects neurons, glia, and endothelial cells, together known as the neurovascular unit. This drug, 3K3A-APC, acts on cells partly via the PAR-1 receptor to induce protection by several mechanisms. Multiple laboratories- using neurobehavioral and histomorphometric endpoints in several animal models-have shown the drug powerfully reduces the effects of experimental stroke, even when administered up to 4 hours after the stroke begins. In human volunteers, only mild and moderate side effects were detected at clinically relevant doses. We now propose to test 3K3A-APC-for the first time-in stroke patients who arrive at the hospital very early and receive thrombolytic treatment. Very low doses will be tried at first, and then progressively higher doses will be tried. Ultimately, we wil determine the maximum tolerated dose (MTD), that is, the largest drug dose that can be given without causing severe side effects. By the end of this study, we hope to determine a dose that is safe and well tolerated by patients suffering acute stroke. Should this study succeed, the next step would be a much larger study to test for possible benefit of 3K3A-APC in stroke patients.