Traumatic brain injury (TBI) is a major healthcare problem that affects millions of people
worldwide. Despite advances in understanding and developing preventative and treatment
strategies using preclinical animal models, clinical trials to date have failed, and a 'magic bullet’ for
effectively treating TBI-induced damage does not exist. Thus, novel pharmacological strategies to
effectively manipulate the complex and heterogeneous pathophysiology of secondary injury mechanisms
are needed. Given that goal, this paper discusses the relevance and advantages of combination
therapies (COMTs) for ‘multi-target manipulation’ of the secondary injury cascade by administering
multiple drugs to achieve an optimal therapeutic window of opportunity (e.g., temporally
broad window) and compares these regimens to monotherapies that manipulate a single target with
a single drug at a given time. Furthermore, we posit that integrated mechanistic multiscale models
that combine primary injury biomechanics, secondary injury mechanobiology/neurobiology, physiology,
pharmacology and mathematical programming techniques could account for vast differences
in the biological space and time scales and help to accelerate drug development, to optimize pharmacological
COMT protocols and to improve treatment outcomes.
Keywords: Combination therapy, secondary injury, brain, multi-target, neurotherapeutic, model.
Rights & PermissionsPrintExport