ANALOGS OF THIAMINE 531 



Oxypyrithiamine reduces the survival time of mice but does not produce 

 polyneuritis, so that it appears to behave like oxythiamine, indicating the 

 importance of the 4'-amino group on the pyrimidine ring for the effects on 

 the nervous system (Cerecedo and Eich, 1955). The 2'-w-butyl analog of 

 thiamine suppresses the growth of rats and leads to polyneuritis, these ef- 

 fects being antagonized by increased thiamine administration, so that this 

 analog superficially acts like pyrithiamine (Emerson and Southwick, 1945). 

 Another substance possibly interfering with thiamine metabolism is 2,4- 

 diamino-5-phenylthiazole (amiphenazole, Daptazole), a drug used as a res- 

 piratory stimulant. Rats on a thiamine-free diet given injections of ami- 

 phenazole and the pyrimidine portion of thiamine in low doses do not show 

 deficiency, indicating some ability to replace the normal thiazole compo- 

 nent, but at higher doses deficiency signs appear sooner (Shulman, 1956). 

 Amiphenazole alone even at high doses produces no effects. An abnormal 

 thiamine analog is apparently synthesized in the animals. The 2-trifluoro- 

 methyl analog of thiamine (trifluorothiamine) administered at 100 mg/kg/ 

 day to mice on the thiamine-deficient diet leads to weight loss, paralysis, 

 convulsions, and an inhibition of the growth of transplanted carcinoma 

 (Barone et al., 1960). It inhibits the growth of Bacillus subtilis more po- 

 tently than does oxythiamine or pyrithiamine; this effect is antagonized 

 by thiamine, but is enhanced by either the pyrimidine or thiazole moieties 

 of thiamine. Further study of this interesting analog will be awaited with 

 anticipation. 



A few miscellaneous observations relative to the pharmacological effects 

 of thiamine analogs on neuromuscular function will be summarized because 

 of the importance of such effects in developing theories of the mechanisms 

 of action. It has long been known that thiamine is involved in the forma- 

 tion of acetylcholine (providing the acetyl radical from pyruvate), and that 

 brain acetylcholine concentration falls during thiamine deficiency; it is pos- 

 sible that some of the effects of the analogs are mediated by a depression 

 of acetylcholine synthesis at synapses. Some have claimed that thiamine 

 is functional in axon conduction through its role in the synthesis of acetyl- 

 choline, and others have reported a release of thiamine during nerve stim- 

 ulation. It is also established that thiamine in rather high concentration 

 inhibits cholinesterase and can, under certain circumstances, augment the 

 action of acetylcholine. Pyrithiamine at 1-3 roM decreases the rates of de- 

 polarization and repolarization during the action potential in frog nerve, 

 whereas oxythiamine at these or higher concentrations produces no effect 

 (Kunz, 1956). This was interpreted as a blocking of the Na+ carrier me- 

 chanism and as evidence for the participation of thiamine in Na+ transport. 

 Depolarization is associated with Na+ entry, but repolarization in nerve is 

 not connected directly to Na+ flux. These concentrations are much higher 

 than occur following administration to animals. The tibialis twitch response 



