Carotid tissue levels of argatroban after direct local delivery during carotid endarterectomy to prevent perioperative cerebral embolism.
OBJECTIVE
Argatroban is a synthetic direct thrombin inhibitor. We applied argatroban locally during carotid endarterectomy to prevent local mural thrombus formation. Although local delivery of argatroban is expected to be effective for inhibition of mural clot formation, there is no report of the evaluation of its clinical effectiveness or local drug concentration in humans.


METHODS
Five mg of argatroban (0.5 mg/ml) was applied twice intraoperatively just after arteriotomy for measurement of intraplaque level of argatroban and during closure of the arteriotomy for preventing thrombus formation. After exposure of the carotid plaque to argatroban for a specified duration (0, 3, 5, or 10 min), argatroban was sufficiently washed with saline and the carotid plaque was removed for measurement of tissue concentration of argatroban. Intraplaque level of argatroban was determined by high-performance liquid chromatography. A second application was performed during closure of the arteriotomy. Argatroban was applied for 10 minutes, followed by washing with saline. Postoperative embolic cerebrovascular complications and carotid restenosis also were investigated to verify the efficacy of direct local application of argatroban.


RESULTS
Tissue levels of argatroban in the carotid plaque after 3, 5, and 10 minutes of direct application were 24.0 +/- 13.7, 31.6 +/- 20.0, and 44.0 +/- 15.1 mug/g, respectively. The concentrations at all time points were significantly elevated compared with the control, and a significant difference in concentration was observed between 3 minutes and 10 minutes. In the present study, concentration at 3 minutes was much higher than the effective tissue levels of argatroban reported in experimental studies. No patient developed postoperative cerebrovascular complications.


CONCLUSIONS
The results suggest that direct local application of argatroban during carotid endarterectomy for at least 3 minutes may deliver high local tissue levels. Argatroban may be effective for prevention of perioperative embolic cerebral complications during carotid endarterectomy.
Kawamata
Takakazu
T
Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical University, Tokyo, Japan. tkawamata@nij.twmu.ac.jp
Okada
Yoshikazu
Y
Kawashima
Akitsugu
A
Hori
Tomokatsu
T
D000328:Adult; D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives; D002339:Carotid Arteries / Q000378:metabolism; D016893:Carotid Stenosis / Q000601:surgery*; D016894:Endarterectomy, Carotid / Q000379:methods*; D005260:Female; D006801:Humans; D020766:Intracranial Embolism / Q000209:etiology / Q000517:prevention & control*; D007432:Intraoperative Period; D008297:Male; D008875:Middle Aged; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012189:Retrospective Studies; D013449:Sulfonamides; D014018:Tissue Distribution
D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban