OILMAN: EFFECTS OF DRUGS ON NERVE ACTIVITY 553 



and Gilman.^ Species vary greatly, both in their response and toler- 

 ance to fluoroacetate. In general, the fluoroacetate ion possesses two 

 main pharmacological actions. In some animals, it affects primarily 

 the heart. Energy metabolism and conduction are so disturbed that 

 pulsus alternans, A-V block, frequent ectopic ventricular beats, and 

 eventually, ventricular fibrillation result. Most herbivorous animals, 

 as well as those species of primates that have been studied, are sus- 

 ceptible to the cardiac actions of the fluoroacetates. The actions of the 

 fluoroacetates on the nervous system are even more striking. Follow- 

 ing a latent period of approximately one hour, animals become progi'es- 

 sively more excited, and eventually exhibit severe epileptiform con- 

 vulsions which continue, uninterrupted, until death. Dogs and cats 

 respond in this manner. Most of those species which exhibit the car- 

 diac actions show no evidence of central stimulation. However, 

 primates, although succumbing to the cardiac action, may show mild 

 epileptiform convulsions. In regard to susceptibility, the lethal con- 

 vulsive dose in the dog is approximately 0.1 mg./Kg. The lethal dose 

 in primates is approximately 100 times as great. 



When one considers the descriptive pharmacology of fluoroacetate in 

 the light of its possible fundamental mechanism of action, certain ques- 

 tions come immediately to mind. Are differences in species response 

 due to different metabolic patterns in their nervous tissue? Observa- 

 tions of Chenoweth and co-workers support the view that the primate 

 myocardium is uniquely dependent upon the utilization of acetate, for 

 adequate function. Similar investigations may reveal that the same 

 is true of the nervous system in the case of the dog and cat. It has 

 been shown by Tepperman and Mazur^ that, in the presence of fluoro- 

 acetate, acetylation is greatly enhanced, presumably because of the 

 high concentration of available acetate. Could this finding possibly 

 be concerned with the convulsive action of the fluoroacetate ion? 

 These are but a few of the problems, pertinent to the nervous system, 

 that have been raised by the preliminary investigations of this drug. 

 By the proper utilization of fluoroacetate as a research tool, it may be 

 possible to relate specific disturbances in the metabolism of nervous 

 tissue to functional abnormalities. In this respect, it is of interest to 

 note that the electroencephalogram obtained during a fluoroacetate- 

 induced convulsion is almost identical to that of a petit mal epileptic 

 seizure. 



The second compound to be discussed is diisopropyl-fluorophosphate. 

 This compound represents a new type of anticholinesterase. Not only 

 does it depart, in its chemical configuration, from previously studied 



