The Importance of Therapeutic Time Window in the Treatment of Traumatic Brain Injury

Abstract

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.

Traumatic brain injury in Mumbai: A survey of providers along the care continuum

“…These themes were often discussed in the context of reducing or increasing complications and delays, which are the two critical components in the final outcome of TBI patients. [ 9 10 11 12 ] When interviewees identified limitations in the major themes, they used teamwork to mitigate workforce shortages and resource allocation, affordable alternatives, and stockpiling to mitigate shortages in equipment and patient finances.…”

Mitochondrial Dysfunction in Traumatic Brain Injury: Management Strategies

“…2,17 It also intervenes in the inhibition of Ca 2+ entry in mitochondria. 18 These drugs have shown improvement in the results once administered 24 hours after the injury. Although it is necessary to note that the most important therapeutic interval in which treatment would result useful are the first 3 hours, therefore, any treatment established after these time will protect against the late insult but will not prevent the insult of early phase.…”

“…10 These data suggest that the drugs that protect the mitochondria have long therapeutic windows, so it is still reliable to administer them hours after the event, obtaining a therapeutic efficacy. 18 Contemplating the functions could be a complementary treatment to reduce the severity of secondary injury after trauma. 15,18…”

“…18 Contemplating the functions could be a complementary treatment to reduce the severity of secondary injury after trauma. 15,18…”

Mild Traumatic Brain Injury is Associated With Effect of Inflammation on Structural Changes of Default Mode Network in Those Developing Chronic Pain 

“…TBI can induce a multitude of in ammatory biomarkers perpetuating the secondary injury to the brain (7,8), which upregulates central nerve system (CNS) excitability contributing to the generation and persistent of concomitant headache (9)(10)(11). Multiple pain disorders have altered grey matter volume (GMV) within the pain matrix (12,13).…”