Prevention of reocclusion by MCI-9038, a thrombin inhibitor, following t-PA-induced thrombolysis in a canine model of femoral arterial thrombosis.
We compared a selective thrombin inhibitor (MCI-9038; Argatroban), a thromboxane A2 (TXA2) receptor antagonist (L-670,596) and a serotonin-2 receptor antagonist (ketanserin) for their ability to hasten clot lysis and delay reocclusion in a canine model of femoral arterial thrombosis. Occlusive thrombosis was induced by insertion of a thrombogenic copper coil. Femoral arterial blood flow velocity (FABFV) was monitored directly and continuously by Doppler flowmetry. Thrombolysis was induced with tissue plasminogen activator (t-PA; 0.8 mg/kg, i.v.), starting 60 min after thrombotic occlusion and continued for 90 min. Ten minutes after occlusion, dogs received an intravenous infusion of either vehicle, MCI-9038 (10 micrograms kg-1 min-1), ketanserin (0.1 mg/kg bolus plus 5 micrograms kg-1 min-1), L-670,596 (1 mg/kg bolus plus 17 micrograms kg-1 min-1) or a combination of L-670,596 and ketanserin. All infusions were discontinued 1 h after stopping the t-PA, and were followed by a 30 min observation period. The times to thrombolysis were similar for all treatments (mean +/- SEM = 47 +/- 3; all groups). MCI-9038 prevented reocclusion, defined as permanent cessation of FABFV during the hour after stopping the t-PA. All dogs receiving MCI-9038 reoccluded within 30 min after stopping its infusion (71 +/- 3 min). Reocclusion occurred in all other dogs, except one vehicle-treated dog and a second dog that received L-670,596 plus ketanserin. Vehicle-treated dogs reoccluded within 23 +/- 8 min. Reocclusion was not delayed significantly by ketanserin, L-670,596 or the combination of the two.(ABSTRACT TRUNCATED AT 250 WORDS)
Mellott
M J
MJ
Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, West Point, PA.
Connolly
T M
TM
York
S J
SJ
Bush
L R
LR
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001157:Arterial Occlusive Diseases / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D005263:Femoral Artery; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D010875:Pipecolic Acids / Q000097:blood / Q000627:therapeutic use*; D012008:Recurrence; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013918:Thrombin Time; D015912:Thrombolytic Therapy / Q000379:methods*; D013927:Thrombosis / Q000188:drug therapy*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; D010959:Tissue Plasminogen Activator; C031942:argatroban