History of drugs for thrombotic disease. Discovery, development, and directions for the future.

Abstract

The history of the antithrombotic agents--aspirin, heparin, warfarin, and the thrombolytics--is a rich and lively odyssey of serendipity, perseverance, vision, and conflict involving a number of striking personalities. The history of aspirin spans ages and continents from Hippocrates' analgesic for women in labor to the rediscovery of the white willow bark by English country scholar Reverend Edward Stone. Bayer chemist Felix Hoffmann reinvented aspirin for his ailing father; suburban physician L.L. Craven pioneered the prophylactic antithrombotic uses of aspirin; and Sir John Vane elucidated aspirin's mechanism of action as the inhibition of prostaglandin synthetase. Heparin was discovered by McLean, working as a medical student in 1915 in search of a pure procoagulant in dog liver. His original impure material differed somewhat from today's heparin, but purified heparin was rapidly accepted for a myriad of clinical uses; to this day, diverse new properties of this complex glycosaminoglycan continue to be elucidated. The oral anticoagulants emerged from veterinary research in the 1920s on a hemorrhagic disorder afflicting cattle that consumed spoiled sweet clover hay. Several chance encounters led Karl Link and his University of Wisconsin team to the identification of dicumarol as the offending agent in 1939 and its widespread therapeutic use by Wright and others in the 1940s. Link later developed warfarin as a rodenticide, but its use in humans soon followed in the 1950s. Vitamin K was discovered in the 1930s; its involvement in the mechanism of the anticoagulant agents was not delineated until the 1970s. The intrinsic ability of clotted blood to liquify and the fibrinolytic properties of normal urine were noted in the 1800s. Tillett and Sherry's group stumbled on the fibrinolytic properties of streptokinase in the 1930s and pioneered the therapeutic use of streptokinase in the 1940s and of urokinase in the 1960s. Several teams found tissue-type plasminogen activator in various body sites beginning in the 1940s, leading to its cloning and widespread use in the 1980s; anisoylated plasminogen-streptokinase activator complex is an example of rational drug design. The discoverers of these diverse agents have not only provided physicians with a potent armamentarium of antithrombotic drugs but also helped elucidate much basic science and vividly demonstrated the merits of perseverance, independent thought, and adherance to the scientific method.

Algorithms for monitoring warfarin use: Results from Delphi Method

“…1 Since then, it stands as the most prescribed oral anticoagulant, widely used for prophylaxis and treatment of venous thromboembolism and complications associated with atrial fibrillation and heart valve replacement. 2,3 New oral anticoagulants, such as direct thrombin inhibitors (DTIs), have been recently approved.…”

Epidemiology and symptomatology of long acting anticoagulant rodenticide poisoning

“…Oxidized coumarin within silage becomes linked to formaldehyde and then to a second coumarin moiety forming dicumarol. [1,2] In the 1940's, as dicumarol was entering clinical use, Karl Link selected # 42 from a number of synthetic dicumarol-based compounds and later named it Warfarin. The name was based upon the acronym for the Wisconsin Alumni Research Foundation in honor of the institution that had funded his research.…”

“…The name was based upon the acronym for the Wisconsin Alumni Research Foundation in honor of the institution that had funded his research. [1][2][3] Various congeners of warfarin were developed through the 1950's and 1960's. These subsequent agents became known as LAARs, (see Table 1).…”

“…[5][6][7][8] LAARs induce anticoagulation through inhibition of the Vitamin K Epoxide Reductase enzyme. [1] This inhibition leads to reduced ability to gamma-carboxylate terminal glutamine residues of Vitamin K Dependent coagulation factors. [9] The absence of this final carboxylation step prevents these factors from binding activated phospholipid membranes, where coagulation reactions proceed to eventually achieve hemostasis (see Figure 1).…”

Functional Genomics and Cardiovascular Drug Discovery

“…1 Similarly, warfarin owes its discovery not to a search for therapeutic anticoagulants, but to studies of a hemorrhagic disease of cattle that devastated the American northern prairie farming community in the 1920s. 2 More recently, cardiovascular drugs have arisen less from chance and more from logical scientific approaches. The development of captopril, for example, depended on an understanding of the active site of the angiotensin-converting enzyme and logical chemical modifications of active site antagonists.…”