Hemorrhagic profile of the fibrinolytic alfimeprase after ischemia and reperfusion.
OBJECTIVE
Recanalization therapies for ischemic stroke have been slow to change clinical practice because of perceived and published risks of hemorrhage associated with lytic administration. We quantified alfimeprase in an acute ischemia-reperfusion model, as compared with recombinant tissue plasminogen activator, with hemorrhagic transformation as the primary endpoint and infarction volume and blood-brain barrier permeability as secondary endpoints.


METHODS
Five groups were studied in a blinded fashion: alfimeprase at doses of 0.03 (n=8), 0.1 (n=11) and 0.3 mg/kg (n=8); recombinant tissue plasminogen activator at 1 mg/kg (n=9); carrier infused controls (n=9). The middle cerebral artery was occluded for 5 hours followed by removal of the suture for reperfusion. Drugs were infused immediately following reperfusion over a 10-minute period. Approximately 24 hours later, the animals were anesthetized and decapitated, and the brains were rapidly harvested and frozen. Serial brain sections were obtained and inspected for hemorrhages. Infarction and blood-brain barrier permeability were also evaluated in additional experiments in control, 0.1 mg/kg alfimeprase and 1 mg/kg recombinant tissue plasminogen activator-treated rats.


RESULTS
The hemorrhagic transformation frequency, neurological deficit and the mortality rate of alfimeprase were significantly lower than for recombinant tissue plasminogen activator at the 0.03 mg/kg dose and not statistically different at the higher doses. Infarction and blood-brain barrier permeability were not significantly different among control, 0.1 mg/kg alfimeprase and recombinant tissue plasminogen activator.


CONCLUSIONS
In this model, alfimeprase, a new fibrinolytic agent, exhibits a profile comparable to recombinant tissue plasminogen activator.
Lu
Aigang
A
Department of Neurology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH, USA.
Kurosawa
Yuko
Y
Luskey
Kenneth
K
Pyne-Geithman
Gail
G
Caudell
Danielle
D
Clark
Joseph
J
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D001929:Brain Edema / Q000188:drug therapy / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005343:Fibrinolytic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008666:Metalloendopeptidases / Q000009:adverse effects* / Q000187:drug effects; D009460:Neurologic Examination; D051381:Rats; D015427:Reperfusion Injury / Q000139:chemically induced* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage
D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D008666:Metalloendopeptidases; C436755:alfimeprase