Margulies Susan S, Kilbaugh Todd, Sullivan Sarah, Smith Colin, Propert Kathleen, Byro Melissa, Saliga Kristen, Costine Beth A, Duhaime Ann-Christine
University of Pennsylvania, Philadelphia, PA.
Brain Pathol. 2015 May;25(3):289-303. doi: 10.1111/bpa.12247.
We have developed the first immature large animal translational treatment trial of a pharmacologic intervention for traumatic brain injury (TBI) in children. The preclinical trial design includes multiple doses of the intervention in two different injury types (focal and diffuse) to bracket the range seen in clinical injury and uses two post-TBI delays to drug administration. Cyclosporin A (CsA) was used as a case study in our first implementation of the platform because of its success in multiple preclinical adult rodent TBI models and its current use in children for other indications. Tier 1 of the therapy development platform assessed the short-term treatment efficacy after 24 h of agent administration. Positive responses to treatment were compared with injured controls using an objective effect threshold established prior to the study. Effective CsA doses were identified to study in Tier 2. In the Tier 2 paradigm, agent is administered in a porcine intensive care unit utilizing neurological monitoring and clinically relevant management strategies, and intervention efficacy is defined as improvement in longer term behavioral endpoints above untreated injured animals. In summary, this innovative large animal preclinical study design can be applied to future evaluations of other agents that promote recovery or repair after TBI.
我们开展了首个针对儿童创伤性脑损伤（TBI）的药物干预的未成熟大型动物转化治疗试验。临床前试验设计包括在两种不同损伤类型（局灶性和弥漫性）中使用多剂量干预措施，以涵盖临床损伤中所见的范围，并采用两种TBI后给药延迟。环孢素A（CsA）因其在多个临床前成年啮齿动物TBI模型中的成功以及目前在儿童中用于其他适应症，被用作我们首次实施该平台的案例研究。治疗开发平台的第1层评估了给药24小时后的短期治疗效果。采用研究前确定的客观效应阈值，将治疗的阳性反应与受伤对照组进行比较。确定有效的CsA剂量以在第2层进行研究。在第2层范式中，在猪重症监护病房中使用神经监测和临床相关管理策略给药，并将干预效果定义为与未治疗的受伤动物相比，长期行为终点有所改善。总之，这种创新的大型动物临床前研究设计可应用于未来对其他促进TBI后恢复或修复的药物的评估。
