Synergism of thrombolytic agents: investigational procedures and clinical potential.

TWO PHYSIOLOGIC plasminogen activators, tissue-type plasminogen activator (t-PA) and single-chain uro-kinase-type plasminogen activator (scu-PA, prouro-kinase),' are presently under clinical investigation as fibrin-specific thrombolytic agents. Although recom-binant t-PA has been shown to be more effective and clot specific for coronary arterial thrombolysis than streptokinase, 2 3its risk/benefit ratio may not be optimal because of only relative fibrin specificity and the occurrence of major bleeding at very high doses.4 Similar limitations will very probably apply to scu-PA.5 Methods to enhance the effectiveness of throm-bolytic therapy may therefore have significant practical importance. One such approach may be the use of synergistic combinations of thrombolytic agents with different mechanisms of fibrin specificity, such as t-PA and scu-PA.6 Synergistic and antagonistic interactions of drugs used for thrombolysis would have significant implications if synergism, as pharmacologically defined, were more marked for the therapeutic than for the toxic effect, or if antagonism were more marked for the toxic than the therapeutic effect. In addition, synergism might reduce the therapeutic dose in man, thus permitting the use of smaller amounts of costly drugs. Optimal exploitation of synergism of thrombolytic agents for clinical use could possibly identify combinations of agents that may result in more optimal risk/ benefit and cost/benefit ratios for thrombolytic therapy than currently obtainable. Synergism, defined as an effect of a combination of agents that is greater than that expected on the basis of their individual dose-effect relationships, is a topic on which great confusion exists in the medical literature. particular combinations of immunosuppressive agents were synergic. Only 14 of these claims were valid, with an additional seven probablyvalid, because most investigators had used fallacious criteria for determining the nature of drug interactions; specifically, they compared the effect of the agents used in combination with the sum oftheir effects when used alone. Chou and Talalay8 have also emphasized that the lack of a theoretical basis for the assessment of effects of drug combinations has hampered the rigorous evaluation of drug interactions. A clear delineation of the clinical utility and limitation of synergistic combinations of thrombolytic agents will therefore depend on the use of a rigorous experimental approach. Methods for demonstrating drug interactions. Several different methods for estimating the effect of additive combinations of drugs have been developed and are in use at present. All of these methods can be shown to be valid in particular sets of circumstances, whereas no single method appears to have totally …