Pharmacological interventions for stroke: failures and future

Given the few options currently available for patients following ischaemic stroke, the recent disappointing failures of several large-scale Phase III clinical trials has made the search for novel therapeutic approaches even more critical. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury which can occur over several hours. Progressive microcirculatory failure following the initial onset of ischaemia may contribute to the expansion of brain injury. Included among the pathophysiological changes that are speculated to occur as a secondary response to the initial ischaemia are free radical production, excitotoxicity (for example, glutamate) disruption of ionic homeostasis (for example, sodium and calcium influx), enzymatic changes, stimulation of the inflammatory process, endothelin release, activation of platelets and leukocytes, delayed coagulation and endothelial dysfunction. All of these pathophysiological reactions could contribute to an increase in local vascular resistance and therefore cause progressive hypoperfusion of the brain following the onset of stroke. The scope of this review will focus on recent clinical failures in addition to agents currently in clinical development, comparing vascular targets to the common neuroprotective strategies.