RATIONALE FOR THE COMBINATION OF ANTI-AGGREGATING DRUGS

Different pathways of platelet activation lead to the exposure of the glycoprotein (GP) IIb/IIIa receptor resulting in binding with fibrinog en and platelet aggregation. The impact of these pathways depends on t he types of agonist present. Most agonists release arachidonic acid (A A), which is metabolised to thromboxane A(2) (TXA(2)). This increases intracellular calcium, which is crucial for exposure of the GP IIb/III a receptor and the release of the dense and/or alpha granule contents. Anti-aggregating drugs act via different mechanisms. Some antagonise pro-aggregating stimuli while others inhibit the metabolism of AA to T XA(2), blocking only one pathway of aggregation and not affecting gran ule content release. Agents that increase cAMP and/or cGMP interfere w ith all known pathways of aggregation and with the release mechanism. Inhibitors of cAMP and/or cGMP specific phosphodiesterases also increa se intracellular nucleotide concentrations and a stimulatory agent tog ether with a phosphodiesterase inhibitor is a very effective combinati on. Finally, GP Ilb/IIIa antagonists abolish the binding of fibrinogen to the platelets, which inhibits platelet aggregation but leaves the release; reaction intact. Different mediators cause aggregation via di fferent pathways, Thus a broader spectrum of anti-aggregating activity can be expected by combining drugs accordingly. Drug combination migh t also increase the chances of interfering more efficiently with the r elease reaction, thereby preventing the release of pro-coagulant and g rowth factors. Synergism might also lead to a reduction in dosage and a decreased risk of side-effects. (C) 1998 Elsevier Science Ltd.