426 COLLECTED STUDIES IN IMMUNITY 



oxidized substances (the analogues of iodic acid) are no longer able 

 to yield up their oxygen to oxidizable combinations when prussic 

 acid is present. (One must think of these highly oxidized substances 

 as transmitters or carriers of oxygen.) Prussic acid poisoning is 

 therefore an internal suffocation of the organs." 



This discovery of contact action constituted the first step toward 

 penetrating the mystery of the action of drugs. This, however, 

 afforded no explanation as to why the substances mentioned ex- 

 hibited an elective action. That was because the link was missing 

 which, according to modern views, is absolutely indispensable, namely 

 the connection between action and distribution in the tissues. I 

 think I am justified in claiming to be the first to recognize the right 

 path, for in 1887, in my article on " The Therapeutic Significance 

 of the Substituting Sulphuric Acid Group" (Therap. Monatshefte, 

 March, 1887), I demonstrated that neurotropic stains are deprived 

 of this property on the addition of the sulfonic-acid group. Even at 

 that time I compared the localization of the dyes and of the alkaloids 

 in the brain with the principle of the shaking-out procedure devised 

 by Stas-Otto, expressing myself as follows: 



"The principle of 'shaking-out' poisons devised by Stas-Otto 

 depends on the fact that basic substances, e.g. alkaloids, etc., are 

 generally firmly combined in acid solutions, and hence extracted 

 with difficulty, whereas the same substances can readily be shaken 

 out of alkaline solutions. Acid substances, of course, exhibit exactly 

 the opposite behavior: they are held back by alkaline media, but 

 readily given up by acid media. If we apply these experiences to 

 the question under discussion we can readily understand why basic 

 dyes (which are not held back by the blood through any chemical 

 affinities) are especially laid hold of by the brain, whereas the acid 

 dyes and the sulfonic acids (which are bound by alkalies of the blood 

 to form salts, and are thus anchored, as it were) show exactly the 

 opposite behavior." 



Besides this I showed that fat tissue behaves like the brain, 

 for a large part of the substances taken up by the brain are taken 

 up also by the fat tissue. In 1891 this question received a fresh 

 impetus, for Hofmeister, Pohl, and also Spiro, called attention to 

 the significance of loose combinations which could readily be dis- 

 sociated. Thus in 1891 Pohl showed that the ability of the red 

 blood-cells to take up chloroform, a fact which Schmiedeberg had 

 demonstrated in 1867, was due to the cholesterm and lecithin which 



