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
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