Old and new natural products as the source of modern antithrombotic drugs

Natural compounds have been the first historical source of antithrombotic compounds (heparin, vitamin K antagonists, streptokinase, urokinase); molecules extracted from plants or animals still provide some of the most original and promising approaches for the discovery of new drugs in this class. In this review, we will briefly describe three examples of current research trends that could lead to the development of new antithrombotic drugs of natural origin. Flavonoids have been shown to be inhibitors of cyclic nucleotide phosphodiesterase; this enzymatic activity is one of the main mechanisms of inhibition of aggregation of blood platelets by flavonoids. Some of these compounds could represent templates for the development of new inhibitors of platelet activation. Garlic ( ALLIUM SATIVUM) has been shown to inhibit platelet aggregation IN VIVO and IN VITRO; a number of active principles has now been identified and their mechanisms of action are currently being explored. An ancient remedy, the medicinal leech ( HIRUDO MEDICINALIS), has been found to contain several potent anticoagulant proteins. Among them, hirudin, a polypeptide of 65 amino acids, has been identified as one of the most potent inhibitors of thrombin. The production of sufficient amounts of hirudin through molecular biology techniques has now allowed the performance of clinical trials. These three examples show that careful consideration of biochemical, ethnopharmacological, or toxicological properties of natural products can still constitute a valuable basis for the development of new drugs.

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This review illustrates natural products as antithrombotic drug sources through three examples—flavonoids as platelet phosphodiesterase inhibitors, garlic antiplatelet principles, and leech-derived hirudin, a 65-amino-acid thrombin inhibitor now producible by molecular biology for clinical trials.

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