R. D. HOTCHKISS 



of substances, whether or not these latter are cUnically useful drugs. 

 We must expect to find that, in intact cells, where diffusion rates, di- 

 electric constants, dissociation constants, and the like may be very 

 different from what they are in ordinary aqueous solutions, the speci- 

 ficities of biochemical systems also will not be the same as in the 

 test tube. The organizational factors which control the various 

 phases of chemical activity in the cell probably grade continuously 

 from slight "crowding" effects of molecule upon molecule which slightly 

 alter diffusion and reaction rates, through major crowding which in 

 effect makes the environment only semiaqueous, and finally all the 

 way to those special arrangements which amount to actual contiguity, 

 or separation, in space, of reactive elements. 



We have attempted to portray as concretely as we are able a 

 general picture of the initial process of drug-protoplasm interaction. 

 It is, more or less, a simple expression in present-day physical terms 

 of views on the mode of drug action which go back at least to 1900. 

 Beginning about that time and throughout the years since, various 

 theories have been put forward, such as those relating narcosis and 

 surface action, associated with the names of Traube, Lillie, and War- 

 burg, among others. Many such hypotheses relating one or another 

 special kind of biological properties to surface behavior have also 

 appeared during this period. Like all old hypotheses, they are old 

 because they have not easily been disproved and discarded, and they 

 have remained hypotheses because they were propounded far in ad- 

 vance of experimental basis. The most inclusive theory is probably 

 that of Ehrlich, who accounted for the phenomena of immunology 

 and pharmacology in terms of combining side chains. Thus, drugs 

 had organotropic or parasitotropic "haptophore" groups able to 

 combine with "chemoreceptor" groups in tissues or parasites; and 

 when so anchored the drugs exerted their effect. To present-day 

 workers this theory has often appeared extravagantly endowed with 

 unsubstantial detail; it is, however, probable that Ehrlich's concepts 

 have remained implicit in the pharmacological thinking of the past 

 few decades, while his terminology has been almost entirely replaced 

 by specific chemical names for reactive groups. 



By far the most significant special theory along these lines is 

 one which accounts for the adsorption of the agent, and also, in a some- 

 what explicit fashion, for the effect which this has upon the cell. In 



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