530 2. ANALOGS OF ENZYME REACTION COMPONENTS 



A concentration of 0.75 n\M inhibits rust development completely and does 

 not exhibit phytotoxicity. Vibrio cholera is inhibited moderately by both 

 oxythiamine and pyrithiamine (Chatterjee and Haider, 1960), Lactobacillus 

 fermentum is inhibited by the imidazole analog of thiamine (Erlenmeyer et 

 al., 1948), and E. coli is inhibited 50% by the methylthio analog of thia- 

 mine at a ratio of 100 with respect to thiamine (Ulbricht and Gots, 1956). 

 Growth inhibition by thiamine analogs has been reviewed by Rogers (1962), 



Toxic and Thiamine-Deficiency Effects in Animals 



Both pyrithiamine and oxythiamine are toxic to animals and produce 

 states apparently related to thiamine deficiency. These analogs are of com- 

 parable potency; in most species pyrithiamine may be slightly more active 

 on a weight basis. The usual daily doses to induce the characteristic toxic 

 reactions and eventual death are usually between 0.01 and 0.1 mg, but this 

 depends on the thiamine intake, the effective ratios of analog/thiamine be- 

 ing around 5 to 50. The sequence of reactions following administration of 

 pyrithiamine to mice or rats may be summarized as: decreased food intake 

 (this may be noted within 24 hr), inactivity and a hunched position, ner- 

 vousness, tremors and occasional convulsions, spasticity followed by weak- 

 ness of the legs, incoordination, and paralysis. Death usually occurs within 

 24 hr after the development of polyneuritis. These are essentially the symp- 

 toms seen in thiamine deficiency but they occur more rapidly after the ana- 

 logs. Full polyneuritis and death may be produced within 5-12 days de- 

 pending on the dose. Pyrithiamine also produces typical thiamine-deficiency 

 polyneuritis in pigeons. The effects of oxythiamine in mice and rats are 

 somewhat different, although death may occur in approximately the same 

 time as from pyrithiamine. There is also anorexia and weight loss, and the 

 animals may become nervous, convulsive, and incoordinated during the 

 first 24 hr, but the later characteristic symptoms of polyneuritis do not 

 occur. Descriptions of the later reactions to oxythiamine have generally 

 been inadequate. In chicks apparently both analogs can induce polyneuritic 

 states. The above summary is derived mainly from the work of Woolley 

 and White (1943 b), Eusebi and Cerecedo (1949), Daniel and Norris (1949), 

 Frohman and Day (1949), Cerecedo et al. (1951), Naber et al. (1954), and 

 Wolfe (1957). 



The differences between the effects of pyrithiamine and oxythiamine in 

 mice and rats have been emphasized by several workers, particularly the 

 absence of polyneuritis during treatment with oxythiamine, and have ini- 

 tiated speculations on the different mechanisms of action. It must be made 

 clear that the toxic effects of oxythiamine are not nonspecific and unre- 

 lated to thiamine function, since the reactions to both analogs may be 

 counteracted by administration of thiamine (Woolley and White, 1943 b; 

 Jones et al., 1948; Daniel and Norris, 1949; Cerecedo et al., 1951; and others). 



