New Frontiers in Clinical Trials Aimed at Improving Outcome Following Traumatic Brain Injury

To date, over 25 clinical trials have been developed to improve outcome by addressing the first two pathologies. None have been successful. However, to our knowledge no one has developed studies to address the clinical relevance of hypoperfusion. Using a model of mixed focal/disuse brain injury, Armstead published that endothelin-1 (ET-1), a powerful vasoconstrictor, plays a critical role in mediating vasoconstriction following traumatic brain injury (TBI). Several laboratories have published that blocking ETrA using BQ-123, a specific ETrA antagonist, improves cerebral blood flow (CBF) after TBI. Kreipke’s laboratory further studied the effects of hypoperfusion on cellular and behavioral outcome following TBI and showed that BQ-123 reduces the extent of hypoperfusion which, in turn, improves both cellular and behavioral outcome following TBI. While these results show promise, enthusiasm for clinical application of this work has been dampened by a lack of a clinically relevant drug that is specific to ETrA (e.g., Bosentan, a mixed ETrA/B antagonist, causes systemic hypotension and, thus, is not a suitable candidate for improving outcome following TBI). However, in 2007 Actelion developed Clazosentan, which is the most highly specific ETrA antagonist currently available (10–100X more selective than previously available drugs [Bosentan, Enrasentan, Tezosentan, Darusentan]). This chapter outlines the seminal aspects of the work related to preclinical studies using ET antagonists as potential therapies for head trauma victims.