442 VITAMIN K GROUP 



to almost universal opinion), hepatitis,^^ menometrorrhagia,^^ "scours" in 

 calves,^^ serofibrinous pleurisy ,^^ thrombocytopenia/^- ^^ (denied by Zuck- 

 er^^), tinea kerion,^^ and whooping cough.^^ The hypoprothrombinemia of 

 tuberculosis may be related to gastroenteric or hepatic involvement and 

 thus may be amenable to vitamin K therapy. ^° 



E. TOXICITY 



Before the advent of dicoumarol, vitamin K was given in doses of only 

 a few milligrams a day. Now, doses of several hundred milligrams are given 

 liberally to overcome dicoumarol's anticoagulant activity; for the most 

 part no toxic effects have been observed. Phelps and Jones'" did note nausea 

 in patients receiving 150 mg. of a menadiol derivative intravenously; with 

 600 mg. doses more severe reactions at times occurred. Intravenous injec- 

 tions of 1 g. of phytyl menadione led to no reactions, but the oxide of this 

 compound in the same dose was followed by a febrile response in one 

 patient. From studies on animals it seems likely that man can tolerate 

 amounts of vitamin K and its analogs much larger than those now being 

 tentatively employed. 



Table VI outlines the toxicity of various menadione preparations given 

 in single doses by various routes; the amount administered in milligrams 

 per kilogram of body weight of the animal is recorded as that causing death 

 in half the animals tested. The immediate cause of death may be circula- 

 tory^^ or respiratory failure.^-* ^^ 



Molitor and Robinson^* demonstrated that lethal doses of menadione and 

 phthiocol were 500 and 350 mg. per kilogram of body weight, respectively, 



82 p. G0tzsche, Ugeskrift Laeger 112, 1753 (1950); H.-O. Mossberg, Brit. Med. J. I. 

 1382 (1952). 



83 T. Baranowski, H. Beck, and S. Liebhardt, Am. Rev. Soviet Med. 3, 173 (1945); 

 R. Gubner and H. E. Ungerleider, Southern Med. J. 37, 556 (1944). 



84 G. W. Anderson, W. M. DuPrd, and J. P. LaMaster, Am. J. Vet. Research 13, 5 

 (1952). 



86 M. A. Josserand, Lyon med. 176, 168 (1946); P. Pichat and H. Boucher, ibid. 176, 

 169 (1946). 



86 F. Groer, T. Baranowski, and J. Rosenbusch, Am. Rev. Soviet Med. 3, 173 (1945). 



87 M. B. Zucker, Proc. Soc. Exptl. Biol. Med. 62, 245 (1946). 



88 L. N^kim, Jr., and P. Polgdr, Acta Dermato-Venereol. 31, 344 (1951); H. Grimmer 

 and S. Rust, Z. Haut- u. Geschlechtskrank . 12, 102 (1952). 



89 J. C. Oyhenart, Dia med. 23, 527 (1951); J. Nemirovsky, Prensa med. argent. 38, 

 1955 (1951); W. B. Pereira da Silva, Rev. brasil. med. 8, 673 (1951). 



90 R. F. Sheely, J. Am. Med. Assoc. 117, 1603 (1941) ; E. Tanner and F. Suter, Schweiz. 

 med. Wochschr. 74, 552 (1944). 



91 S. Ansbacher, W. C. Corwin, and B. G. H. Thomas, J. Pharynacol. Exptl. Therap. 

 75, 111 (1942). 



92 R. H. K. Foster, Proc. Soc. Exptl. Biol. Med. 45, 412 (1940). 



93 M. B. Shimkin, J. Pharmacol. 71, 210 (1941). 



94 H. Molitor and H. J. Robinson, Proc. Soc. Exptl. Biol. Med. 43, 125 (1940). 



I 



