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BackgroundThere are no drugs presently available to treat traumatic brain injury (TBI). A variety of single drugs have failed clinical trials suggesting a role for drug combinations. Drug combinations acting synergistically often provide the greatest combination of potency and safety. The drugs examined (minocycline (MINO), N-acetylcysteine (NAC), simvastatin, cyclosporine A, and progesterone) had FDA-approval for uses other than TBI and limited brain injury in experimental TBI models.Methodology/Principal FindingsDrugs were dosed one hour after injury using the controlled cortical impact (CCI) TBI model in adult rats. One week later, drugs were tested for efficacy and drug combinations tested for synergy on a hierarchy of behavioral tests that included active place avoidance testing. As monotherapy, only MINO improved acquisition of the massed version of active place avoidance that required memory lasting less than two hours. MINO-treated animals, however, were impaired during the spaced version of the same avoidance task that required 24-hour memory retention. Co-administration of NAC with MINO synergistically improved spaced learning. Examination of brain histology 2 weeks after injury suggested that MINO plus NAC preserved white, but not grey matter, since lesion volume was unaffected, yet myelin loss was attenuated. When dosed 3 hours before injury, MINO plus NAC as single drugs had no effect on interleukin-1 formation; together they synergistically lowered interleukin-1 levels. This effect on interleukin-1 was not observed when the drugs were dosed one hour after injury.Conclusions/SignificanceThese observations suggest a potentially valuable role for MINO plus NAC to treat TBI.

OBJECTIVE The antifibrinolytic agent tranexamic acid (TXA) has demonstrated clinical benefit in trauma patients with severe bleeding but its effectiveness in patients with traumatic brain injury (TBI) is unclear. We conducted a systematic review to evaluate the following research question: In ED patients with or at risk of intracranial hemorrhage secondary to TBI, does TXA compared to placebo improve patients’ outcomes? METHODS MEDLINE, EMBASE, CINAHL and other databases were searched for randomized (RCT) or quasi-RCT studies that compared the effect of TXA to placebo on outcomes of TBI patients. The main outcomes of interest included mortality, neurological function, hematoma expansion, and adverse effects. We used “Grading quality of evidence and strength of recommendations” (GRADE) to assess the quality of trials. Two authors independently abstracted data using a data collection form. Results from studies were pooled when appropriate. RESULTS Out of 1030 references identified through the search, two high-quality RCTs met inclusion criteria. The effect of TXA on mortality had a pooled relative risk (RR) of 0.64 (95%CI, 0.41–1.02), on unfavorable functional status a RR of 0.77 (95%CI, 0.59–1.02), and on intracranial hemorrhage progression a RR of 0.76 (95%CI, 0.58–0.98). No serious adverse effects (such as thromboembolic events) associated with TXA group were reported in the included trials. CONCLUSION Pooled results from the two RCTs demonstrated statistically significant reduction in intracranial hemorrhage progression with TXA and a non-statistically significant improvement of clinical outcomes in ED patients with TBI. Further evidence is required to support its routine use in patients with TBI.