Pharmacologic interventions for stroke: looking beyond the thrombolysis time window into the penumbra with biomarkers, not a stopwatch.
OBJECTIVE
The majority of pharmacological agents for stroke were developed based on the assumption that neurological deficits will be reduced upon the successful interruption of biochemical mechanisms leading to neuronal death. Despite significant evidence of preclinical efficacy, none of these agents succeeded. They either failed to demonstrate efficacy in the clinic or their development was halted for safety, strategic, or commercial reasons.


RESULTS
This "neuroprotection strategy" has focused primarily on targets in the neurotoxic environment that occurs under ischemic conditions. In many cases, these agents were designed to tackle events that are known to start almost immediately after onset of ischemia, which is far before a realistic therapeutic time window opens for most, if not all, patients with stroke. In other instances, they were evaluated beyond a realistic timeframe in which one could expect significant salvageable tissue or penumbra to exist. Surprisingly, most of these agents were not evaluated in conjunction with strategies for improving perfusion to the affected tissue, indicating an overoptimistic assumption that neuroprotection alone could be sufficient to halt injury caused by an abrupt interruption of brain blood flow.


CONCLUSIONS
We provide a constructive translational medicine perspective about how one could improve the drug development process with the hope that the probability for success can increase in our quest to establish a novel therapy for stroke.
Chavez
Juan C
JC
Department of Translational Medicine, Wyeth Research, Collegeville, PA 19426, USA. chavezj@wyeth.com
Hurko
Orest
O
Barone
Frank C
FC
Feuerstein
Giora Z
GZ
D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D019610:Cytoprotection / Q000187:drug effects* / Q000502:physiology; D018450:Disease Progression; D015195:Drug Design; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D017211:Treatment Failure
D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents