Mohamadpour Maliheh, Whitney Kristen, Bergold Peter J
Department of Neurology, State University of New York Downstate Medical Center, Brooklyn, NY, United States.
Department of Physiology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY, United States.
Front Neurosci. 2019 Jan 23;13:07. doi: 10.3389/fnins.2019.00007. eCollection 2019.
Traumatic brain injury (TBI) is a major cause of death and disability. Despite its importance in public health, there are presently no drugs to treat TBI. Many reasons underlie why drugs have failed clinical trials, one reason is that most drugs to treat TBI lose much of their efficacy before patients are first treated. This review discusses the importance of therapeutic time window; the time interval between TBI onset and the initiation of treatment. Therapeutic time window is complex, as brain injury is both acute and chronic, resulting in multiple drug targets that appear and disappear with differing kinetics. The speed and increasing complexity of TBI pathophysiology is a major reason why drugs lose efficacy as time to first dose increases. Recent Phase III clinical trials treated moderate to severe TBI patients within 4-8 h after injury, yet they turned away many potential patients who could not be treated within these time windows. Additionally, most head trauma is mild TBI. Unlike moderate to severe TBI, patients with mild TBI often delay treatment until their symptoms do not abate. Thus, drugs to treat moderate to severe TBI likely will need to retain high efficacy for up to 12 h after injury; drugs for mild TBI, however, will likely need even longer windows. Early pathological events following TBI progress with similar kinetics in humans and animal TBI models suggesting that preclinical testing of time windows assists the design of clinical trials. We reviewed preclinical studies of drugs first dosed later than 4 h after injury. This review showed that therapeutic time window can differ depending upon the animal TBI model and the outcome measure. We identify the few drugs (methamphetamine, melanocortin, minocycline plus N-acetylcysteine, and cycloserine) that demonstrated good therapeutic windows with multiple outcome measures. On the basis of their therapeutic window, these drugs appear to be excellent candidates for clinical trials. In addition to further testing of these drugs, we recommend that the assessment of therapeutic time window with multiple outcome measures becomes a standard component of preclinical drug testing.
创伤性脑损伤（TBI）是死亡和残疾的主要原因。尽管其在公共卫生领域具有重要性，但目前尚无治疗TBI的药物。药物临床试验失败有许多原因，其中一个原因是大多数治疗TBI的药物在患者首次接受治疗之前就已失去大部分疗效。本综述讨论了治疗时间窗的重要性；即TBI发作与开始治疗之间的时间间隔。治疗时间窗很复杂，因为脑损伤既是急性的又是慢性的，导致多个药物靶点以不同的动力学出现和消失。TBI病理生理学的速度和复杂性不断增加，这是药物随着首次给药时间的增加而失去疗效的主要原因。最近的III期临床试验在损伤后4 - 8小时内治疗中度至重度TBI患者，但却拒绝了许多无法在这些时间窗内接受治疗的潜在患者。此外，大多数头部创伤是轻度TBI。与中度至重度TBI不同，轻度TBI患者通常会延迟治疗，直到症状没有减轻。因此，治疗中度至重度TBI的药物可能需要在损伤后长达12小时内保持高效；然而，治疗轻度TBI的药物可能需要更长的时间窗。TBI后的早期病理事件在人类和动物TBI模型中以相似的动力学进展，这表明时间窗的临床前测试有助于临床试验的设计。我们回顾了损伤后4小时后首次给药的药物的临床前研究。本综述表明，治疗时间窗可能因动物TBI模型和结果测量而异。我们确定了少数几种药物（甲基苯丙胺、促黑素、米诺环素加N - 乙酰半胱氨酸和环丝氨酸），它们在多种结果测量中显示出良好的治疗时间窗。基于它们的治疗时间窗，这些药物似乎是临床试验的优秀候选药物。除了对这些药物进行进一步测试外，我们建议用多种结果测量来评估治疗时间窗成为临床前药物测试的标准组成部分。
