title: Combination Therapies for Traumatic Brain Injury: Retrospective Considerations.
abstract: Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests. Four studies had equivocal results because of a lack of sensitivity of the outcome assessments. One study demonstrated worse results with the combination in comparison with monotherapies. While specific research findings are reported elsewhere, this article provides an overview of the study designs, insights, and recommendations for future research aimed at therapy development for TBI.
authors.affiliation: 1 Department of Bioengineering, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Susan
authors.initials: S
authors.lastname: Margulies
authors.affiliation: 2 Department of Pharmacy, Pharmaceutics, and Neurological Surgery, University of Washington , Seattle, Washington.
authors.forename: Gail
authors.initials: G
authors.lastname: Anderson
authors.affiliation: 3 Department of Emergency Medicine, Emory University , Atlanta, Georgia .
authors.forename: Fahim
authors.initials: F
authors.lastname: Atif
authors.affiliation: 4 Institut of Neuroscience Cognitive and Integrative of Aquitaine (INCIA), University of Bordeaux , Bordeaux, France .
authors.forename: Jerome
authors.initials: J
authors.lastname: Badaut
authors.affiliation: 5 Safar Center for Resuscitation Research and Department of Critical Care Medicine, University of Pittsburgh School of Medicine , Pittsburgh, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Clark
authors.affiliation: 6 Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy , Pittsburgh, Pennsylvania.
authors.forename: Philip
authors.initials: P
authors.lastname: Empey
authors.affiliation: 7 Fresenius Kabi USA, LLC , Lake Zurich, Illinois.
authors.forename: Maria
authors.initials: M
authors.lastname: Guseva
authors.affiliation: 8 Department of Psychology, Southern Illinois University , Carbondale, Illinois.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoane
authors.affiliation: 9 Department of Anesthesiology and Critical Care, Children's Hospital of Philadelphia , Philadelphia, Pennsylvania.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Huh
authors.affiliation: 10 Department of Pharmaceutical Sciences, University of Kentucky , Lexington, Kentucky.
authors.forename: Jim
authors.initials: J
authors.lastname: Pauly
authors.affiliation: 11 Department of Neurobiology and Anatomy, Drexel University College of Medicine , Philadelphia, Pennsylvania.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Raghupathi
authors.affiliation: 12 Center on Aging, University of Kentucky , Lexington, Kentucky.
authors.forename: Stephen
authors.initials: S
authors.lastname: Scheff
authors.affiliation: 3 Department of Emergency Medicine, Emory University , Atlanta, Georgia .
authors.forename: Donald
authors.initials: D
authors.lastname: Stein
authors.affiliation: 3 Department of Emergency Medicine, Emory University , Atlanta, Georgia .
authors.forename: Huiling
authors.initials: H
authors.lastname: Tang
authors.affiliation: 13 One Mind , Seattle, Washington.
authors.forename: Mona
authors.initials: M
authors.lastname: Hicks
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001930:Brain Injuries / Q000188:drug therapy*; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination / Q000379:methods*; D008297:Male; D051379:Mice; D051381:Rats
keywords: pharmacological interventions; preclinical therapeutic development; treatments