388 THE BIOCHEMISTRY OF B VITAMINS 



increased peripheral blood flow 94 and a rise in cutaneous temperature. 

 The reaction is not considered to be a "frank toxic manifestation" 95 in 

 view of the low dosage that evokes it and its absence on nicotinamide 

 administration, the latter being about twice as toxic as the free acid. 

 Approximately 30 mg of niacin per day orally may be sufficient to arouse 

 the reaction, while 10 mg intravenously or 60 mg intramuscularly are 

 frequently effective. At present, 16-18 mg of nicotinic acid are generally 

 added to each pound of flour in this country, and there has been at least 

 one report of a flushing reaction from this source. In general it seems 

 that there is a great individual variation in response, that all individuals 

 react to some dosage, and that the manifestation is a harmless one. It 

 does however make the amide the vitamin isotel of choice, since oral 

 doses as high as 500 mg are without a nitroid effect. 



The pharmacological effects of niacin and many other closely related 

 pyridine derivatives have been intensively studied, and it should be men- 

 tioned that the diethylamide of nicotinic acid, coramine or nikethamide, 

 is a widely used respiratory stimulant. 96, 97 Nicotinic acid, as regards its 

 flushing action, has been likened to histamine, acting in a manner 

 antagonistic to epinephrine. Nicotinic acid has little or no effect on the 

 blood pressure or pulse rate however, its effects on peripheral blood flow 

 being apparently local ones. It is without effect on the autonomic ganglia, 

 isolated rabbit intestine, or isolated guinea pig uterus. Nicotinic acid has 

 been compared with its amide, the mono- and diethyl amides, and pyridine 

 as regards their effects on curare, prostigmine, and acetylcholine action 

 on the quadriceps and soleus muscles of cats anaesthetized with nem- 

 butal. 98 These results are indicated in Table 33. 



Table 33. Some Pharmacological Effects of Niacin and Similar Compounds 



. Effect on ■- 



Derivative Curare Effect Prostigmine Effect Acetylcholine Effect 



Pyridine antagonistic reinforcing enhancing 



Nicotinic acid antagonistic antagonistic enhancing 



Nicotinamide antagonistic reinforcing enhancing 



Ethylnicotinamide reinforcing reinforcing enhancing 



Diethylnicotinamide reinforcing reinforcing 



It has similarly been convenient to compare the toxicity of niacin with 

 that of many structurally similar compounds. As regards chronic toxicity, 

 it seems that doses as high as 2 gm/kg daily for several months do not 

 affect dogs, rats, or chicks. 99 Brazda and Coulson have determined the 

 subcutaneous LD 50's of a number of pyridine derivatives for rats, 100 

 and their results are summarized in Table 34. Unna 101 has similarly 

 found the LD 50 of niacin for mice and rats to be from 4-5 gm/kg 

 subcutaneously and 5-7 gm/kg orally, and the toxicity of nicotinamide 



