554 ANNALS NEW YORK ACADEMY. OF SCIENCES 



anticholinesterase agents, but it also differs in its fundamental mecha- 

 nism of action, in that the inhibition of cholinesterase is irreversible. 

 What is more, diisopropyl-fluorophosphate is highly lipoid-soluble and 

 rapidly gains access to nervous tissue. 



In diisopropyl-jfiuorophosphate, the neurophysiologist has at his 

 command a research tool in which the fundamental mechanism of ac- 

 tion is known. Thus, if the major premise of my introductory re- 

 marks is to hold true, the application of this compound to problems of 

 neurophysiology should help to prove or disprove fundamental con- 

 cepts of nerve function. 



The advantages of an irreversible anticholinesterase, as a research 

 tool, are at once evident. Following the action of diisopropyl-fluoro- 

 phosphate, the cholinesterase activity of a tissue can be restored only 

 by resynthesis of enzyme. Moreover, the agent can be administered, 

 and the response of a tissue studied. Following this, the tissue can 

 be removed and ground ; the homogenate appropriately diluted ; and the 

 absolute cholinesterase activity determined ; an approach which cannot 

 be employed with a compound such as physostigmine, due to the re- 

 versible nature of its inhibition. Thus, for the first time, a highly quan- 

 titative approach to the problems of the role of cholinesterase and 

 acetylcholine in the transmission of the nerve impulse is available. 



Diisopropyl-fluorophosphate has already followed the path from 

 the laboratory to the clinic. Comroe and associates,^ at the University 

 of Pennsylvania, and Harvey and co-workers,^^ at Johns Hopkins, have 

 employed this agent in the treatment of Myasthenia gravis. The 

 therapeutic efficacy of this type of compound, as well as its limitations, 

 has already been demonstrated. Of even greater interest, will be the 

 more fundamental data, from these studies, which may shed light on 

 the defect in transmission associated with this myopathy. 



Basic laboratory studies, employing diisopropyl-fluorophosphate as 

 a research tool, have also begun. I should like to report, in some detail, 

 the experiments of Crescitelli and co-workers,® designed to elucidate 

 the possible role of acetylcholine in the conduction of the nerve impulse 

 along the nerve fiber. The background literature to this problem has 

 recently been summarized by Loewi^ and by Feldberg,^ and need not 

 be repeated here. Mention should be made, however, of the studies 

 of Cowan,^ Lorente de No,^" Hertz," and Cantoni and Loewi,^^ in 

 which either physostigmine or acetylcholine failed to exert a significant 

 effect on transmission in the nerve fiber. However, the availability 

 of an irreversible inhibitor of cholinesterase, which afforded an oppor- 

 tunity to correlate nerve function with quantitative data on cholin- 



