The therapeutic window for efficient post-treatment of focal cerebral
ischaemia with the fibrinogen lowering agent ancrod was studied by mag
netic resonance imaging (MRI) in spontaneously hypertensive rats (SHR)
. Ancrod or vehicle solution (0.9% NaCl) were i.v. infused (0.12 IU/kg
per min) via implanted mini pumps starting 0.5, 1.5, 3 or 6 h after p
ermanent proximal middle cerebral artery occlusion and lasting until b
rain mapping by multislice T2-weighted magnetic resonance imaging in v
ivo 24 h after middle cerebral artery occlusion. Plasma fibrinogen con
centrations were measured before middle cerebral artery occlusion, bef
ore pump implantation and after magnetic resonance imaging. Total brai
n lesion volumes as determined by magnetic resonance imaging 24 h afte
r middle cerebral artery occlusion were 131 +/- 36 (188 +/- 28)(), 15
1 +/- 39 (194 +/- 39)(), 147 +/- 44 (207 +/- 33)(*) and 209 +/- 60 (2
14 +/- 42) mm(3) in rats with 0.5, 1.5, 3 and 6 h, respectively, delay
of ancrod treatment (means +/- S.D., 8-11 animals/group, correspondin
g control groups in parentheses, P- < 0.05). Continuous i.v. ancrod i
nfusions reduced plasma fibrinogen levels significantly (P < 0.05) in
all ancrod-treated groups as compared to vehicle-treated controls unti
l the end of the experiments 24 h after middle cerebral artery occlusi
on. In conclusion, significant cerebroprotection was achieved even whe
n the onset of ancrod therapy for lowering of the plasma fibrinogen le
vel was delayed for up to 3 h. To the best of our knowledge no drug ef
ficacy has been reported so far with a therapeutic window of 3 h after
permanent middle cerebral artery occlusion in spontaneously hypertens
ive rats suggesting that ancrod may provide an efficient therapy of ac
ute human stroke. (C) 1997 Elsevier Science B.V.