title: Synthesis of Findings, Current Investigations, and Future Directions: Operation Brain Trauma Therapy.
abstract: Operation Brain Trauma Therapy (OBTT) is a fully operational, rigorous, and productive multicenter, pre-clinical drug and circulating biomarker screening consortium for the field of traumatic brain injury (TBI). In this article, we synthesize the findings from the first five therapies tested by OBTT and discuss both the current work that is ongoing and potential future directions. Based on the results generated from the first five therapies tested within the exacting approach used by OBTT, four (nicotinamide, erythropoietin, cyclosporine A, and simvastatin) performed below or well below what was expected based on the published literature. OBTT has identified, however, the early post-TBI administration of levetiracetam as a promising agent and has advanced it to a gyrencephalic large animal model--fluid percussion injury in micropigs. The sixth and seventh therapies have just completed testing (glibenclamide and Kollidon VA 64), and an eighth drug (AER 271) is in testing. Incorporation of circulating brain injury biomarker assessments into these pre-clinical studies suggests considerable potential for diagnostic and theranostic utility of glial fibrillary acidic protein in pre-clinical studies. Given the failures in clinical translation of therapies in TBI, rigorous multicenter, pre-clinical approaches to therapeutic screening such as OBTT may be important for the ultimate translation of therapies to the human condition.
authors.affiliation: 1 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.affiliation: 2 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.|3 Bruce W. Carter Department of Veterans Affairs Medical Center , Miami, Florida.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Bramlett
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Shear
authors.affiliation: 5 Department of Neurological Surgery, Brain Trauma Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: C Edward
authors.initials: CE
authors.lastname: Dixon
authors.affiliation: 6 Department of Neurosciences, University of Messina , Messina, Italy .
authors.forename: Stefania
authors.initials: S
authors.lastname: Mondello
authors.affiliation: 2 Department of Neurological Surgery, The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami , Miami, Florida.
authors.forename: W Dalton
authors.initials: WD
authors.lastname: Dietrich
authors.affiliation: 7 Center for Innovative Research, Center for Neuroproteomics and Biomarkers Research, Banyan Biomarkers, Inc. , Alachua, Florida.
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hayes
authors.affiliation: 8 Center of Neuroproteomics and Biomarkers Research, Department of Psychiatry and Neuroscience, University of Florida. Gainesville, Florida.
authors.forename: Kevin K W
authors.initials: KK
authors.lastname: Wang
authors.affiliation: 9 Center for Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Poloyac
authors.affiliation: 9 Center for Pharmaceutical Sciences, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Empey
authors.affiliation: 10 Department of Anatomy and Neurobiology, Virginia Commonwealth University , Richmond, Virginia.
authors.forename: John T
authors.initials: JT
authors.lastname: Povlishock
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mountney
authors.affiliation: 1 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Megan
authors.initials: M
authors.lastname: Browning
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Ying
authors.initials: Y
authors.lastname: Deng-Bryant
authors.affiliation: 5 Department of Neurological Surgery, Brain Trauma Research Center, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Hong Q
authors.initials: HQ
authors.lastname: Yan
authors.affiliation: 1 Department of Critical Care Medicine, Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Travis C
authors.initials: TC
authors.lastname: Jackson
authors.affiliation: 11 Banyan Biomarkers , Alachua, Florida.
authors.forename: Michael
authors.initials: M
authors.lastname: Catania
authors.affiliation: 11 Banyan Biomarkers , Alachua, Florida.
authors.forename: Olena
authors.initials: O
authors.lastname: Glushakova
authors.affiliation: 11 Banyan Biomarkers , Alachua, Florida.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Richieri
authors.affiliation: 4 Brain Trauma Neuroprotection/Neurorestoration, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research , Silver Spring, Maryland.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Tortella
mesh_terms: D000818:Animals; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000639:trends*; D008297:Male; D009462:Neurology / Q000379:methods / Q000639:trends; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018696:Neuroprotective Agents
keywords: biomarker; controlled cortical impact; drug; fluid percussion; micropig; penetrating ballistic-like brain injury; pre-clinical modeling; rat; reproducibility; therapy; traumatic brain injury