The Direct Thrombin Inhibitor Melagatran and Its Oral Prodrug H 376/95: Intestinal Absorption Properties, Biochemical and Pharmacodynamic Effects

A 75-year-old man with diabetes mellitus is found to have chronic atrial fibrillation, and warfarin therapy is begun for the prevention of thromboembolic stroke. How should the anticoagulant therapy be initiated and managed?

https://www.nejm.org/doi/suppl/10.1056/NEJMcp025373/suppl_file/nejm_schulman_675sa1.pdf

Clinical practice. Care of patients receiving long-term anticoagulant therapy.

Hepatobiliary carcinoma associated with primary sclerosing cholangitis and chronic ulcerative colitis

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.

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

The pharmacodynamics and pharmacokinetics of the oral direct thrombin inhibitor ximelagatran and its active metabolite melagatran: a mini-review

It has been known for many years by veterinarians and cattle raisers that cattle fairly frequently and for no apparent reason bleed considerably and perhaps fatally. Studies of this condition were made originally and independently in 1921 by Schofield1in Canada and by Roderick2in this country. They determined that this hemorrhagic disease arises from eating improperly cured hay or silage made from the common sweet clovers. It was recognized early that if the hemorrhagic manifestations had not proceeded too far the hemorrhage could be controlled by withdrawal of the spoiled hay from the diet or by the injection of freshly drawn blood serum of healthy animals.3At first it was thought that the liver was damaged by the ingested spoiled hay, but this could not be confirmed by Roderick. However, he noted that the delayed coagulability of the blood involved a reduction in the prothrombin content

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=jama&articleId=258678&pdfFileName=jama_120_13_004.pdf

A PREPARATION FROM SPOILED SWEET CLOVER: [3,3′-Methylene-Bis-(4-Hydroxycoumarin)] Which Prolongs Coagulation and Prothrombin Time of the Blood: A Clinical Study

Carcinoma of the extrahepatic bile ducts.

Exactly fifty years ago the first recorded successful attempt was made to remove a carcinoma of the ampulla of Vater by radical resection. After this operation by Halsted 1 only sporadic attempts at radical resection were made, most of them being unsuccessful. Then, in 1935, Whipple. Parsons and Mullins 2 devised a technic for operation in two stages which could be undertaken as a curative and not a palliative measure. The advent of vitamin K permitted one stage radical resection to be executed with less risk than had accompanied certain palliative procedures before this means of correction of deficiency of prothrombin was available. The important observations made by Dragstedt 3 concerning the physiology of the pancreas and the surgical accomplishments of Brunschwig, 4 Crile, 5 Trimble and his associates, 6 Hunt. 7 Pearse, 8 Cattell, 9 Orr 10 and others soon gave the members of the profession confidence in the

Radical resection of head of pancreas and total pancreatectomy

In spite of the existence of accurate diagnostic procedures and intensive educational campaigns directed toward both physician and patient, many carcinomas of the large intestine become far advanced before a diagnosis is made. In 1924, after reviewing the records of 1,937 patients who had carcinoma of the rectum or sigmoid, Buie 1 made the statement that 1 of every 5 of these patients had been operated on for hemorrhoids or had been treated symptomatically for some type of organic disease, other than the carcinoma. The aforementioned author has made this statement repeatedly since that time. It is remarkable, however, that during the period of their symptoms just as many patients as heretofore continue to receive treatment for some supposed condition of the rectum or colon other than the carcinoma, which thus remains undiscovered. The purpose of our study was to determine the nature of the treatment in relation to the

John M. Waugh

Papers

A PREPARATION FROM SPOILED SWEET CLOVER: [3,3′-Methylene-Bis-(4-Hydroxycoumarin)] Which Prolongs Coagulation and Prothrombin Time of the Blood: A Clinical Study

Carcinoma of the extrahepatic bile ducts.

Radical resection of head of pancreas and total pancreatectomy

Carcinoma of the large intestine: diagnostic errors in relation to location of the lesion.