Combination treatment for acute ischemic stroke: A ray of Hope?
BACKGROUND
With the implementation of thrombolysis, a large number of distinct pharmacological agents are now under consideration for the treatment of acute ischemic stroke, with disappoiting early results. Because the processes that ultimately lead to ischemic cell death involve a variety of pathophysiologic pathways, it is likely that combinations of agents may be necessary to positively affect neurological outcome. We review the general strategies under consideration for reduction of ischemic injury in the central nervous system, the types of possible interactions between compounds, and the experimental evidence showing effective combination therapies.


RESULTS
Reduction of ischemic injury has been attempted by the following pharmacologic mechanisms: thrombolysis, neuroprotection, and perfusion/reperfusion enhancers. There is experimental evidence that the combination of thrombolytic therapy with a neuroprotective agent is additive in some ischemic models, as is the combination of a thrombolytic with an agent that facilitates reperfusion (thromboxane A(2) receptor antagonist and neutrophil adhesion/activation inhibition). Combinations of neuroprotective agents such as glutamate antagonists and calcium channel antagonists may be additive, and other combinations of neuroprotective agents, such as a glutamate antagonist with a gamma-aminobutyric acid (GABA) agonist, have even shown synergism in a rat stroke model. It has also been suggested that lower doses of toxic drugs may be used together to yield a positive neurologic outcome. Successful demonstration of additive or synergistic effects of pharmacologic agents in ischemia will depend on (1) the model used (well below a maximal "ceiling effect"); (2) the timing of drug administration; (3) the doses of the drugs used; and (4) the primary neurologic endpoint used. (Infarction size requires prolonged survival.)


CONCLUSIONS
It appears from preclinical studies that some combinations of pharmacotherapeutic agents may be beneficial in cerebral ischemia, but rigorous evaluation is needed before initiating clinical trials.
Fagan
S C
SC
College of Pharmacy and Allied Health Professions, Wayne State University Center Detroit, MI. USA; Department of Pharmacy Services Center for Stroke Research Henry Ford Hospital and Health Science Center, Detroit, MI, USA; Department of Neurology, Center for Stroke Research Henry Ford Hospital and Health Science Center, Detroit, MI, USA; Department of Neurosciences, University of California, San Diego, CA. USA.
Bowes
M P
MP
Berri
S A
SA
Zivin
J A
JA