768 XII. VITAMINS K 



One interesting (compound which has a powerful anticoagulant action 

 is the so-called coumachlor, which is 3-(a-p-chlorophenyl-/3-acetylethyl)- 

 4-hydroxycumarol ; it is useful as a rodenticide, because of its anticoagulant 

 action. Reiff and Wiesmann'^' discovered that this compound, when in- 

 gested, prolonged the prothrombin time and resulted in hemorrhage and 

 death. This effect can be counteracted by vitamin Ki, but not by mena- 

 dione.^^- Dam and S0ndergaard^^^ reported that coumachlor is more 

 effective as an anticoagulant than is dicumarol, in chicks and rats. 



One mechanism of action of dicumarol and related compounds has been 

 ascribed to an injury to the liver which prevents prothrombin synthesis. 

 If such were the case, the injury could be counteracted by vitamin K. 

 Evidence supporting the liver injury theory includes the observation that 

 overdoses produce fatty livers in rabbits, ^^* and central necrosis of the 

 liver in rats;'^^ in animals with damaged livers the effect of dicumarol is 

 accentuated.^^® Moreover, when the liver is already damaged, smaller 

 doses of dicumarol produce the same results as do larger doses in the normal 

 animal.^" Dicumarol in small doses stimulates fibrinogen production, 

 while larger doses, as in the case of other hepatoxic agents, depress fibrino- 

 gen synthesis. ^^^ Moreover, the fact that the amount of vitamin K neces- 

 sary to reverse the action of dicumarol followed no fixed ratio led Glavind 

 and Jansen^^^ to assume that liver injury w^as the determining factor. 



A second theory to explain the mechanism of the anticoagulants is that 

 a competition exists between vitamin K and dicumarol. Collentine and 

 Quick'®° postulated the existence of a mutual competition between vitamin 

 K and dicumarol for the prothrombinogenic enzyme systems. They 

 arrived at their conclusion because of the minuteness of the doses of 

 vitamin Ki or of dicumarol which were found to counteract each other in 

 dogs depleted of vitamin K. Molho, Moraux, and Meunier'®^ base their 

 opinion upon the similarity in structure between the hemorrhagic agents 



'6' M. Reiff and R. Wiesmann, Acta Tropica, 8, 97-130 (1951) 



'*2 C. Montigel and R. Pulver, II. Congres. International de Biochimie, Paris, 1952, 

 Resumes des Communications, p. 220. 



'*' H. Dam and E. S0ndergaard, Acta pharmacol. el toxical., 9, 137-147 (1953). 

 '" K. F. Jansen, Nord. med., 20, 1993-1997 (1943). 



165 C. L. Rose, P. N. Harris, and K. K. Chen, Proc. Soc. Exptl. Biol. Med., 50, 228-232 

 (1942). 



166 J. L. Bollman and F. W. Preston, /. Am. Med. Assoc, 120, 1021-1025 (1942). 

 >67 D. Roller and O. Miidrak, Z. ges. exptl. Med., 114, 75-90 (1944). 



158 U. D. Irish and L. B. Jaqiies, Am. J. Physiol., 143, 101-104 (1945). 

 1" J. Glavind and K. F. Jansen, Acta Phtjsiol. Scand., S, 173-182 (1944). 

 loo G. E. Collentine and A. J. Quick, Am. J. Med. Sci., 222, 7-12 (1951). 

 1" D. Molho, J. Moraux, and P. Meunier, Bull. soc. chim. hioL, 30, 037-042 (1948); 

 P. Meunier, Ibid., 884-891 (1948). 



