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，也是世界上导致死亡的主要原因之一。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%的患者对溶血疗法有反应，因此开发新的、有效的中风治疗方法成为当务之急。大脑由多种类型的细胞组成：神经元、神经胶质细胞和内皮细胞等；中风时，大脑每分钟损失120万个神经元。在过去，候选的中风治疗方法仅针对神经元，但对患者无效。我们现在提议测试一种新药，它能有效地保护神经元、神经胶质细胞和内皮细胞，这些细胞被称为神经血管单元。这种药物，3K3A-APC，部分通过PAR-1受体作用于细胞，通过几种机制诱导保护。多个实验室——在几个动物模型中使用神经行为学和组织形态学的终点——已经表明，即使在中风开始4小时后给药，这种药物也能有效地减少实验性中风的影响。在人类志愿者中，仅在临床相关剂量下检测到轻度和中度副作用。我们现在建议首次在早期到达医院并接受溶栓治疗的脑卒中患者中检测3k3a - apc。一开始将尝试极低剂量，然后逐步尝试更高剂量。最终，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，我们希望确定急性中风患者安全且耐受良好的剂量。如果这项研究成功，下一步将是一项更大规模的研究，以测试3K3A-APC对中风患者的可能益处。

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.