386 THE BIOCHEMISTRY OF B VITAMINS 



Thiamine. The pharmacodynamic action of thiamine may best be 

 described as "curare-like." 51 In frogs, rats, and dogs, except for the 

 dosage, c?e:c£ro-tubocurarine and thiamine have been demonstrated to have 

 almost identical effects. Rapid intravenous injection of 50 mg/kg of 

 thiamine hydrochloride into dogs causes respiratory paralysis, hypoten- 

 sion, bradycardia, and vasodilation, but if respiration is maintained these 

 effects are transient. Toe contractions resulting from stimulation of the 

 isolated sciatic nerve are prevented by both thiamine and dextro-tubo- 

 curarine, although the muscle still responds to direct stimulation. Similar 

 effects may be demonstrated on the exposed sciatic nerve and gastro- 

 cnemius muscle of frogs. These results seem closely related to the 

 symptoms following administration of lethal doses to experimental 

 animals — weakness, tetany, labored breathing, and death from respiratory 

 failure. Thiamine has found some use in the treatment of labor pains 52 

 in intramuscular doses of 60 mg. 



The lethal doses of thiamine by intravenous administration are 125, 

 250, 300 and 350 mg/kg for the mouse, rat, rabbit and dog respectively, 

 and the toxic subcutaneous and oraT doses are about six and forty times 

 as high respectively. There is no apparent cumulative effect. The thera- 

 peutic index (ratio of. therapeutic dose to minimum lethal dose) is there- 

 fore about 600 for mice, 5000 for rats, and 70,000 for dogs. Haley 54 has 

 carefully determined thiamine toxicity for the mouse and rabbit and finds 

 that for the mouse the intravenous LD 50 * is 84.24 mg/kg, with a stand- 

 ard error of ±1.14 for the mononitrate salt. Intraperitoneally it is 387.3 

 mg/kg ±1.65; and 329.8 ±3.93 for the hydrochloride. For the rabbit the 

 average intravenous lethal dose of the mononitrate is 112.58 mg/kg and 

 for the hydrochloric 117.45 mg/kg. He quotes Molitor as having found 

 the intravenous hydrochloride toxicity for the mouse to be 85 mg/kg. 

 The rapidity of the onset of thiamine pharmacological activity is such 

 as to largely preclude any possibility of action other than interference 

 in some enzyme system. Death seems to result generally from paralysis 

 of the respiratory center of the medulla, 55, 56 and the administration of 

 thiamine by cisternal puncture 57 or direct application to the cerebral 

 cortex 5S produces particularly marked effects. 



Thiamine toxicity in man is well known and presents a number of 

 special problems. 59 It appears reasonably certain that the untoward 

 effects reported as resulting from thiamine administration in man result 

 either from sensitization and the resulting allergic type of response or in 

 a very few cases from some inherent susceptibility to this compound. All 

 the cases reported in this regard, including two deaths 60, 61 and several 

 near deaths 62 had histories of extensive previous thiamine therapy, and 

 * The dose that produces death in 50 per cent of the test animals given that dose. 



