Combination Therapy for Multi-Target Manipulation of Secondary Brain Injury Mechanisms

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.