Preventive effect of synthetic serine protease inhibitor, FUT-175, on cerebral vasospasm in rabbits.
The effect of the synthetic multiserine protease inhibitor FUT-175 on cerebral vasospasm after subarachnoid hemorrhage (SAH) was investigated in rabbits. The SAH in rabbits was simulated by a single injection of autologous arterial blood into the cisterna magna, and, for 7 days, the caliber of each basilar artery was examined several times via angiogram. In 10 SAH rabbits, the peak of the arterial narrowing was observed on Day 2. In this model, the effect of intravenous administrations of FUT-175 was examined. Twenty-seven SAH rabbits were randomly divided into three groups, and 3 doses of 1, 2, or 3 mg of FUT-175 were administered intravenously. Angiographic arterial narrowing on Day 2 in nontreated SAH rabbits (Control) was 35% compared with 21, 5, and 14% in rabbits treated with a total of 3 (Group A; n = 9), 6 (Group B; n = 13), and 9 mg (Group C; n = 5) of FUT-175, respectively. There were statistically significant differences in the arterial calibers between Group A and the Control on Days 1 and 2, between Group B and the Control from days 1 to 4, and between Group C and the Control from days 1 to 4. In three other rabbits, after vasospasm reached its maximum on Day 2, no vasodilatory effect was observed when a total of 6 mg of FUT-175 was administered intravenously. The results indicate that the inhibition of the plasma serine protease cascades at an early stage of SAH prevents the development of cerebral vasospasm.(ABSTRACT TRUNCATED AT 250 WORDS)
Yanamoto
H
H
Department of Neurosurgery, Kyoto University Medical School, Japan.
Kikuchi
H
H
Okamoto
S
S
Nozaki
K
K
D000818:Animals; D001550:Benzamidines; D002533:Cerebral Angiography; D002536:Cerebral Arteries / Q000473:pathology; D003167:Complement Activation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005342:Fibrinolysis / Q000187:drug effects; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation; D002546:Ischemic Attack, Transient / Q000209:etiology / Q000517:prevention & control*; D016234:Kallikrein-Kinin System / Q000187:drug effects; D008297:Male; D011817:Rabbits; D011897:Random Allocation; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications
D001550:Benzamidines; D006146:Guanidines; D015842:Serine Proteinase Inhibitors; C032855:nafamostat