648 13. REVERSAL OF INHIBITION 



(I)l may be equated with the lethal dose in moles per liter. This lethal 

 dose must increase as the inhibition required to kill increases. 



When a reactivator of the iV-alkylpyridine aldoxime type is present, the 

 following reaction also occurs: 



EI + R 4 E + T (13-85) 



where the distinction between EI and EX has been ignored. A similar treat- 

 ment leads to an expression for (I)^. If this value for (I)^ in the presence 

 of the reactivator is divided by the value for (I)^ in the absence of any 

 reactivator, one obtains what Green called the therapeutic efficiency of 

 the reactivator. 



(I)l.r _ 1 + i_6 



(I). 



. r hJ-R) 1_ 



' L ^.(I)l 1 - 



(13-86) 



where (I)j ^ is the lethal dose in the presence of the reactivator. This is 

 an approximate expression inasmuch as certain assumptions had to be 

 made to simplify the equation for practical use. For example, it is assumed 

 that the inhibitor and reactivator are homogeneously distributed through- 

 out the body, and that the concentrations of the inactivator and reacti- 

 vator are constant over a short interval. The expression is valid when -i^ 

 is high and the therapeutic efficiency is less than 20. Some interesting de- 

 ductions may be made from Eq. 13-86. The therapeutic efficiency depends 

 on the inhibition in such a manner that the efficiency increases as the lethal 

 degree of inhibition increases. Also the therapeutic efficiency is propor- 

 tional to the eight-tenth power of 1/(1 — i^) whereas without the reacti- 

 vator, (I)l is proportional to In 1/(1 — i^). Therefore, the presence of the 

 reactivator causes the level of required enzyme inhibition, i^, to be very 

 important. If i^^ can be changed in any, way, as by the application of atro- 

 pine to block some of the effects of the rise in acetylcholine concentration, 

 the therapeutic efficiency for a particular reactivator may be much im- 

 proved. Although this approach is, to some extent, qualitative because of 

 the unknown factors that must be involved in the poisoning, it is a first 

 step towards a more accurate and comprehensive treatment based on fur- 

 ther experimentation. 



