Combination of the thromboxane receptor antagonist, sulotroban (BM 13.177; SK&F 95587), with streptokinase: demonstration of thrombolytic synergy.
We examined the ability of the prostaglandin endoperoxide/thromboxane A2 antagonist, sulotroban (BM 13.177; SK&F 95587) to enhance the thrombolytic efficacy of a minimally effective thrombolytic dose of streptokinase. A critical stenosis sufficient to just abolish the hyperemic response to a 20-sec total occlusion was placed on the left circumflex coronary artery of anesthetized open chest dogs using an adjustable screw occluder clamp. Thrombi were formed by applying a 150 microA anodal current to a wire placed within the lumen of the left circumflex just proximal to the screw occluder clamp. After thrombus formation, animals were given either streptokinase (20,000 I.U. bolus + 2,000 I.U./min x 180 min, N = 10), streptokinase + sulotroban (5 mg/kg bolus + 5 mg/kg/hr, N = 10), streptokinase + heparin (300 I.U./kg bolus + 100 I.U./kg/hr, N = 9) or streptokinase + heparin + sulotroban (N = 9). Plasma thromboxane A2 level (as measured by the metabolite, thromboxane B2) was not significantly reduced by any treatment, whereas the dose of sulotroban used completely abolished U46619-induced ex vivo platelet aggregation. Of 10 animals receiving streptokinase alone, only 1 reperfused at 55 min after the start of the streptokinase infusion. Conversely, 9 of 10 animals receiving streptokinase + sulotroban reperfused at 79.4 +/- 10.5 min poststreptokinase (P less than .05). When animals were treated with heparin before streptokinase administration, 8 of 9 animals receiving the streptokinase + heparin combination reperfused in an average of 66.8 +/- 8.6 min after the start of streptokinase infusion.(ABSTRACT TRUNCATED AT 250 WORDS)
Kopia
G A
GA
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.
Kopaciewicz
L J
LJ
Ohlstein
E H
EH
Horohonich
S
S
Storer
B L
BL
Shebuski
R J
RJ
D000818:Animals; D004285:Dogs; D004357:Drug Synergism; D005343:Fibrinolytic Agents; D006439:Hemodynamics / Q000187:drug effects; D006493:Heparin / Q000008:administration & dosage; D066298:In Vitro Techniques; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D010976:Platelet Count / Q000187:drug effects; D011982:Receptors, Prostaglandin / Q000187:drug effects*; D017482:Receptors, Thromboxane; D012039:Regional Blood Flow / Q000187:drug effects; D013300:Streptokinase / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage*; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors*; D013929:Thromboxane B2 / Q000097:blood
D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011982:Receptors, Prostaglandin; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013929:Thromboxane B2; D013928:Thromboxane A2; C040624:sulotroban; D006493:Heparin; D013300:Streptokinase