INHIBITION OF PLATELET-AGGREGATION AS A SURROGATE MARKER

Using acetylsalicylic acid-dipyridamole, a combined thromboxane recept or antagonist-thromboxane synthase inhibitor, and a fibrinogen recepto r antagonist as examples, this article discusses the predictive value of several methods that may be employed in the evaluation of antiaggre gatory effects and their suitability as surrogate markers for the plan ning of patient studies. Platelet aggregation in various ex vivo tests and the effects of drugs on these tests were investigated using plate let aggregation in platelet-rich plasma and in whole blood, and in thr ombus formation on a thrombogenic surface. Drug-induced inhibition of platelet aggregation is based on the modulation of metabolic processes or interactions at the membrane-receptor level. These effects must be assessed by methods adapted specifically to each mode of action, for example, mediator synthesis inhibition (cyclooxygenase), thromboxane r eceptor antagonism-thromboxane synthase inhibition, or fibrinogen rece ptor blockade. Thus a combination of both general and specific methods adapted to the respective mode of action of the test substance can se rve as surrogate markers of drug efficacy for the efficient planning o f clinical trials.