Clinical Experience With Coumarin Anticoagulants Warfarin and Warfarin Sodium

Abstract

SYNTHESISof the 3-substituted-4-hydroxycoumarin anticoagulant No. 42, 3-(a phenyl-\g=b\-acetylethyl)-4-hydroxycoumarin,* was first accomplished and its action studied in Dr. Karl Paul Link's laboratory.\s=d\ The compound has been generically termed "warfarin" and its sodium salt termed "warfarin sodium." The sodium derivative4 is readily water-soluble, and the solutions are stable. Structural formulae of these compounds appear in Figure 1. Warfarin, when given orally, and warfarin sodium, when given orally or intravenously, produce hypoprothrombinemia, as do the other 3-substituted-4-hydroxycoumarin compounds.Interesting experimental data regarding warfarin sodium and warfarin in the rat have been made available by Eble,\s=dd\working in Link's laboratory. These workers believe the rat to be the preferred experimental animal in the study of 4-hydroxycoumarin anticoagulants, as the response of the rat is most closely parallel to that of the human. Eble found that when massive oral doses, of 100 mg. per kilogram, of warfarin were given the rat its presence in the plasma could be detected spectrophotometrically (Beckman, 308 mm.) within four hours. The plasma concentration time curve was not affected by simultaneous doses of vitamin Ki (250 mg. per kilogram). However, in adequate doses vitamin Ki gave complete protection from the toxicity and anticoagulant activity of warfarin and was more effective in this respect against warfarin than against cyclocumarol.Lower doses of warfarin resulted in proportionately lower concentrations of warfarin in the plasma. There was no difference between warfarin and its sodium salt in the rate of appearance in the blood stream or in the ultimate concentration when they were given orally. It was found that warfarin sodium given intravenously rapidly diffused through the rat body and was found in maximum concentration in the muscle, plasma, and liver five minutes after the injection. When the gastric pyloric sphincter

Oral Anticoagulant Therapy in Patients Receiving Haemodialysis: Is It Time to Abandon It?

“…The first medicine from this group was dicoumarol, isolated by Karl Link at the University of Wisconsin in 1941 [15]. However, they really started to be commonly used in 1950, when a more effective and bioavailable medicine was introduced—warfarin [16]. Their mechanism of action consists in inhibiting the activity of the vitamin K reductase complex, which makes the carboxylation of the residues of glutamic acid in the N-terminal fragments of different proteins impossible.…”

Clinical Evaluation of "Miradon"

“…Since the introduction of dicoumarol about 17 years ago (Butt et al, 1941 ;Wright and Prandoni, 1942;Overman et al, 1942), a number of hydroxycoumarin and indanedione derivatives, causing depression of the prothrombin activity of blood, have become available for use as anticoagulants. In addition to dicoumarol, these include ethyl biscoumacetate (" tromexan ") (Tulloch and Gilchrist, 1951 ; Burke and Wright, 1951), phenindione (" dindevan ") (Jaques et al, 1950), phenylpropylhydroxycoumarin (" marcoumar ") (Bourgain et al, 1954), cyclocoumarol (" cumopyran ") (Hanson et al, 1951), and, more recently, warfarin (Clatanoff et al, 1954) and nicoumalone (" sintrom") (Weiner et al, 1956). They all suffer the disadvantage of being potentially dangerous and require frequent estimations of the prothrombin time for their control.…”

Clinical Experience With the Anticoagulant Panwarfin (Warfarin Sodium)

“…The derivatives of phenindione suffer from the same disadvantages plus the possibility of side reactions such as granulocytopenia, hepatitis, jaundice, skin rash and anemia. Ethyl biscoumacetate (Tromexan) presents difficulty in adjusting dosage, requires frequent prothrombin determinations, has a tendency to &dquo;escape&dquo; from a once-established therapeutic range and has high required doses.1, 2, 3 From the above, it becomes evident that a &dquo;nearly ideal&dquo; anticoagulant did not exist until lately. Such an anticoagulant should create a predictable and uniform effect with a prompt action and a smooth curve of hypoprothrombinemia.…”