Dose-Dependent Inhibition of Experimental Arterial Thrombosis by Carbenicillin and Ticarcillin

Abstract

Drugs that inhibit platelet (PL) function may be useful in the prophylaxis of arterial thrombosis. We have shown that carbenicillin (CARB) and ticarcillin (TIC) cause dose-dependent inhibition of PL aggregation (AGG) in dogs, and that high doses of either of these penicillins significantly decrease the frequency of thrombosis in pronase (PN) injected arteries of dogs. Using this model we have compared the thrombosis prophylaxis effectiveness of these penicillins administered in low dose (250mg/Kg/24 hr, s.c.) (LD-P) versus high dose (750mg/Kg/24 hr, s.c.) (HD-P). Treatment for 3 to 7 days with LD-P resulted in marked inhibition of ADP-induced AGG, but had little or no effect on collagen-induced AGG, while HD-P routinely inhibited collagen as well as ADP-induced AGG. Control dogs were untreated, and their PL function remained normal. Thrombosis with total occlusion occurred in 13 of 15 arteries in control dogs, while only 3 of 29 segments totally occluded in HD-P treated dogs (χ2 = 21.7; p<0.001). However, total occlusion developed in 13 of 20 arteries in dogs receiving LD-P (χ2 = 1.1; p<0.3). The frequency of occlusion was significantly lower (p<0.001) following treatment with HD-P than LD-P. Aspirin (ASA) administration in low dose (650mg/24 hr p.o.) (LD-A) or high dose (2600mg/24 hr p.o.) (HD-A) uniformly inhibited collagen-induced PL AGG, but total occlusion developed in 11 of 16 PN injected arteries in dogs given LD-A, and in 10 of 12 arteries in dogs given HD-A. We conclude that CARB and TIC are effective experimental antithrombotic agents. Their effect is dose-dependent and closely correlated with inhibition of collagen-induced PL AGG. In high doses CARB and TIC are more effective than ASA in preventing PN induced arterial thrombosis. CARB and TIC warrant further study as potentially useful antithrombotic agents in humans.