Delayed argatroban treatment reduces edema in a rat model of intracerebral hemorrhage.
OBJECTIVE
Studies indicate that thrombin plays an important role in intracerebral hemorrhage (ICH)-induced edema formation. Although thrombin is produced as the blood clots, it may be bound to fibrin and only gradually released from the clot. The time window for administration of a thrombin inhibitor to reduce ICH-induced edema is unknown. Whether this time window extends beyond the period when a thrombin inhibitor might exacerbate rebleeding is also unknown.


METHODS
This study examines (1) whether argatroban, an inhibitor of both free and fibrin-bound thrombin, can reduce edema formation after intracerebral infusion of 100 micro L of blood in the rat; (2) the therapeutic time window for argatroban; and (3) whether argatroban promotes rebleeding in a model in which ICH was induced by intracerebral injection of collagenase.


RESULTS
Intracerebral infusion of blood caused a marked increase in perihematomal water content. Intracerebral injection of argatroban 3 hours after ICH caused a significant reduction in edema measured at 48 hours (80.9+/-1.0% versus 82.6+/-0.8%; P<0.01). The systemic administration of high-dose argatroban (0.9 mg/h) starting 6 hours after ICH also significantly reduced edema (80.3+/-1.1% versus 82.0+/-1.3% in vehicle controls; P<0.05). There was no protection when the onset of argatroban administration was delayed to 24 hours after ICH or if a lower dose of argatroban (0.3 mg/h) was used. Argatroban did not increase collagenase-induced hematoma volume when given into the clot after 3 hours or given systemically at 6 hours.


CONCLUSIONS
Our data suggest that argatroban may be an effective therapy for ICH-induced edema.
Kitaoka
Takuji
T
Department of Neurosurgery, University of Michigan, Ann Arbor, USA.
Hua
Ya
Y
Xi
Guohua
G
Hoff
Julian T
JT
Keep
Richard F
RF
D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D001120:Arginine / Q000031:analogs & derivatives; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control*; D002543:Cerebral Hemorrhage / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006454:Hemoglobins / Q000032:analysis; D007263:Infusions, Parenteral; D008297:Male; D008845:Microinjections; D010875:Pipecolic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013238:Stereotaxic Techniques; D013449:Sulfonamides; D013997:Time Factors; D016896:Treatment Outcome; D014867:Water / Q000032:analysis
D000991:Antithrombins; D006454:Hemoglobins; D010875:Pipecolic Acids; D013449:Sulfonamides; D014867:Water; D001120:Arginine; C031942:argatroban