770 XII. VITAMINS K 



an antihemorrhagic action resembling that of vitamin K. Moreover, 

 asymmetric phenylindanedione and several other single molecular com- 

 pounds are active hemorrhagic agents. ^'^* 



It is impossible to determine definitely which is the best theory to ex- 

 plahi the behavior of these anticoagulants. Woolley'^*''^® indicates that 

 the dicumarol-vitamin K antagonism differs from characteristic analog 

 competitions. Thus, vitamin Iv counteracts dicumarol over a limited 

 dosage range, and the inhibition index is not constant within this range. 

 Moreover, an index of less than 1 .0 is much lower than is noted in the usual 

 analog competitions. Actually an index as low as 0.4 occurs in the rat, in 

 which case 10 mg. of dicumarol are inhibited by 25 mg. of vitamin K. 



Lee et al^"- and Spinks and Jaques'"^ were able to obtain further facts 

 about the action of dicumarol by the use of dicumarol labeled in the 

 methylene bridge with C'^. When this product was fed, the isotope was 

 found almost exclusively in the liver, gall-bladder, urine, and feces, while 

 degradation products appeared in the urine. This would indicate that 

 the hepatic cell was involved. The metabolism of dicumarol was not 

 accelerated by the administration of vitamin K.^''^ The active compounds 

 are excreted by the kidneys, as is indicated by the report of Bollman and 

 Preston ^'^^ that the activity of the anticoagulant is prolonged when the 

 treated animal is nephi-ectomized. When the hemorrhagic agent (phenyl- 

 indanedione) is rapidly excreted, due to a decreased glomerular capillary 

 resistance, the duration of the anticoagulant action is greatly reduced. '^^''^^ 

 Seegers'^'' reviewed the effect of drugs on blood clotting. 



A large number of investigators'^^"'^^ have observed that the hypopro- 

 thrombinemia induced by the dicumarol type of anticoagulants can be 



164 P. Mevinier, C. Mentzer, and A. Vinet, Helv. Chim. Ada, 29, 1291-1297 (1946). 



165 D. W. Woollev, Physiol. Revs., 27, .308-3.3:} (1947). 



166 D. W. Woollev, Admnces in EnzymoL, 6, 129-146 (1946). 



16' S. Shapiro, W. Weiiier, and G. Simson, New Engl. J. Med., 243, 775-779 (1950). 



168 p. Gley and J. Delor, Bull. soc. chim. bioL, 30, 891-896 ( 1948). 



169 J. Badin, C. Mentzer, J. Moraiix, and P. Meunier, Compt. rend. soc. bioL, 144, 871- 

 872(1950). 



™ W. H. Seegers, Phannacol. Revs., 3, 278-344 (1951 ). 



I'l C. S. Davidson and H. MacDonald, Neiv Engl. J. Med., 229, 353-355 (1943). 

 1" D. F. James, T. D. Johnson, and S. Burnett, Am. J. Med., 11, 244 (1951). 

 1" T. B. Van Itallie, R. P. Gever, and F. J. Stare, /. Clin. Invest., 30, 680 (1951). 

 "4 D. M. Watkin, T. B. Van'ltallie, W. B. Logan, R. P. Gever, C. S. Davidson, and 

 F. J. Stare, J. Lab. Clin. Med., 37, 269-271 (1951 ). 



™ A. Rehbein, A. Jaretzki, and D. V. Habif, Ann. Surg., 135, 454-469 (1952). 



"6 F. Roller, A. Loeliger, and F. Diickert, Rev. d'hemat., 7, 156-167 (1952). 



1" F. Roller and H. Jakob, Schweiz. med. Wochschr., 83, 476-480 (1953). 



i'8 C. G. Guttas, W. C. Molonev, and H. S. Sise, Blood, 8, 276-281 (1953). 



1" K. W. G. Brown and R. L. MacMillan, Am. J. Med. Sci., 225, 495-500 (1953). 



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