PRESIDENTIAL ADDRESS. 299 



Of course in mammals, and in the chick after hatching, the arginin, in the 

 protein of the food and the creatin in the flesh, when it is eaten, must serve as 

 an ample supply of guanidin, so ample in fact that probably a very consider- 

 able part of arginin is at once decomposed by arginase into urea. 



ii. Methyl-guanidin. a normal constiluent of the body. 



Methyl-guanidin is a normal constituent of flesh and of liver as was shown 

 by Smorodinzew. Miss Henderson '" found in the muscle of cats an average of 

 0-0839 per cent, of free guanidin or methyl-guanidin. It occurs in normal human 

 urine and in that of the dog and horse." In the blood of normal dogs 

 it is present in hardly detectable quantities, i- 



In tetania parathyreopriva the increase in the guanidin content of the blood 

 is accompanied by an increased excretion in the urine, and a similar increase in 

 the urine has been found in the idiopathic tetany of children. In two cases of 

 tetany in adults Sharpe found guanidin as di-methyl-guanidin in amounts easily 

 demonstrable in the urine. 



Methyl-guanidin like uric acid thus seems to be partly excreted as such and 

 partly, when in larger quantities, to undergo some change. 



iii. P/tysiolor/ical Action of Guanidin. 



Guanidin and its methyl derivative, which in future I shall speak of together 

 as guanidin, are substances of great pharmacological activity. Their action was 

 first investigated by Gergens and Baumann in 1876. They described in frogs 

 fibrillar twitching of the muscles due to a peripheral action and tonic extensor 

 spasms due to an action on the spinal cord. They point out that in mammals 

 the tonic spasms are more marked than the fibrillar twitching of the muscles. 



Subsequent investigators have confined their attention chiefly to the peripheral 

 action and considerable discussion has arisen as to the exact point of action 

 of the substance. 



When we were investigating tetania parathyreopriva, Burns was engaged 

 on a study, following up the suggestion of Pekelharing. of the possible relation 

 of the guanidin part of the creatin molecule to the tone of muscle. The extra- 

 ordinary similarity of the symptoms produced to those of experimental tetany 

 suggested to ne the possibility that the condition of tetany might be related to 

 some disturbance of the guanidin metabolism, and led to a more careful investi- 

 gation of the action of guanidin and methyl-guanidin. 



We have already arrived at the conclusion that tetany is due to a toxic 

 substance in the blood, since the symptoms can be temporarily removed by 

 bleeding and transfusing with normal sodium chloride solution, a fact which 

 cannot be explained on the view that the symptoms are due to a decrease in 

 the calcium of the blood as had been suggested by 'McCallum. 



We found that the administration of guanidin and methyl-guanidin pro- 

 duced symptoms identical with those of parathyreoidectomy. There was the same 

 direct stimulation of the outgoing spinal neurons to the muscles leading to 

 tremors, jerkings and general convulsions and when large doses were directly 

 applied to the spinal cord a paralytic condition similar to that which some- 

 times supervenes in tetania parathyreopriva. There was the same increased 

 excitability of the nerves to electrical stimulation, followed, after large doses, 

 by a curare-like action, a condition also observed in clinical tetany after 

 convulsions. 



Koch had described the occurrence of guanidin with other bases in the urine 

 of the dog after removal of the parathyreoids. In our series of experiments 

 Burns and Sharpe found a most marked increase in the guanidin or methyl- 

 guanidin content of the blood (loc. rit.). The method is long and tedious and 

 there is con.?iderable chance of loss, although in test analvsis it was found to 

 give a good return of the added base. But the differences between the guanidin 

 content of normal blood and of blood after parathyreoidectomy and in children 

 suffering from tetany was found to be very marked. 



Wishart '^ further found that the muscles of the frog immersed in the serum 

 from the blood of dogs and cats after parathyreoidectomy frequently mani- 

 fested the tremors and the characteristic change in contraction which are 

 produced by the action of guanidin. The possibility of using this biological 



