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progress has been made in stroke prevention, diagnosis, and
therapy. It could be argued that this progress has been driven by
our increased understanding of the pathophysiology of stroke.
Experimental animal models of stroke have shed light on the
molecular mechanisms of cellular damage and repair and have
revealed numerous potential therapeutic targets. Yet, experimental
models of neurotherapeutic agents have not directly translated into
effective clinical treatments.
The troubling aspect is that in over 120 human phase II and
60 phase III stroke trials, only one neuroprotective agent (tissue
plasminogen activator also known as t-PA) has led to improved
outcomes (
4, 5
). The failure of experimental therapies to translate
from the bench to the bedside has been the source of much discus-
sion (
6, 7
). However, it remains unclear why neuroprotective
agents that are effective in animal models fail in human trials.
To explain the lack of congruency between the animal and
human studies, some authors point to the methodological quality
of animal studies (
8
) while others focus on the inability of current
animal models to capture the complexity of the human condition
(
6
). On the other hand, some authors suggest that the failing may
actually be in the conduct of human clinical trials; they fail due to
the lack of analytical rigor used in animal studies (
9
). Recognizing
the need to robustly evaluate neuroprotective agents at the pre-
clinical stage and to reduce the risk of failure in large, expensive
clinical trials, academicians, and industry researchers convened the
Stroke Therapy Academic Industry Roundtable (STAIR). The
outcome of this meeting was a set of guidelines that are meant to
optimize and potentially standardize preclinical studies of neuro-
protective therapies. The key points for investigators engaged in
preclinical neuroprotection studies are (
7
):
Adequate dose-response curves with drug levels correspond-
●
ing to the minimal effective and maximally tolerated doses
Studies of therapeutic time windows which should show ben-
●
efi t when the drug is administered over delayed time periods
after stroke onset
Adequate physiological monitoring performed in a random-
●
ized, blind fashion. These should be reproducible in two dif-
ferent laboratories, one of which should be independent of the
sponsoring institution
Outcome measures, including both functional outcome as well
●
as infarct volume, both measured in short and long-term studies
Studies should be completed in smaller species, typically in
●
permanent occlusion models, unless reperfusion is necessary
for the drug effect. For fi rst-in-class drugs, larger species should
be used for confi rmation
Data should be peer-reviewed
●
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